Draft v 3.8 for consultation
Ensuring equitable access to complex molecular
diagnostic testing for cancer patients
This document contains a series of consultation questions.
Please use the form provided to respond by 20th June to:
tracy.parker@dh.gsi.gov.uk
26 April 2012
Molecular diagnostic testing
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CONTENTS:
1.
Executive summary
2.
Introduction




3.
The case for change






4.
Patient access to tests

KRAS tests

EGFR tests

Haematological tests
Consistency and reliability of testing
Quality of sample processing
Building partnerships with industry
Improving research capacity
Cost/benefit analysis
Proposed approach






5.
Background
Scope
Current activity
Current commissioning for molecular tests
Identification of new tests
Approval of new tests
Commissioning of testing services
Delivery of testing services
Monitoring
Links to research
Implementation
Annexes:
A
B
C
D
E
F
G
Attendees at stakeholder meeting June 2011
Exclusions from scope
Treatments associated with molecular targets: current and future
Survey of current testing activity
Calculation of potential testing need for vemurafenib and crizotinib
Methodology for calculation of unmet testing need
Glossary of terms
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Executive Summary
1.1
This document seeks comments about what needs to be done to ensure that
we have an efficient and effective system for molecular testing of cancers.
1.2
In January 2012, the Secretary of State for Health confirmed the
Government’s commitment to take forward plans to develop a commissioning
and funding structure led by the NHS Commissioning Board1 to enable the
efficient delivery of high quality molecular testing of cancers.
1.3
Whilst molecular testing is already being undertaken in the NHS and private
sector, the absence of a nationally agreed quality assurance process and
variation in commissioning and funding of tests have led to the slow uptake of
new tests, fragmented provision and issues in ensuring consistent quality of
the tests provided. There is currently a gap in provision and we cannot be
confident that patients are getting the appropriate tests.
1.4
Developing a coherent national structure will enable new tests to be
introduced quickly and ensure that all appropriate patients have access to high
quality tests that can indicate which treatment is best for them.
1.5
This paper makes a number of proposals, including that:
1.6
1

commissioning of the new structure is delivered at a national level with
rigorous value and quality requirements that will ensure a high quality
and cost effective service, and that delivery against these requirements
will be monitored by the NHS Commissioning Board.

new tests are evaluated for use in a timely fashion. A small topic
identification panel to consider the utility of NICE evaluating proposed
topics.

the NICE Diagnostic Assessment Programme will lead on assessing new
molecular tests for cancer and they will need to provide clear guidelines
on the patient populations to be tested and at what point testing should
be done in the patient care pathway.

a temporary steering group chaired by the National Cancer Director will
oversee implementation of the proposals, working with industry and
commissioners to facilitate partnerships between industry and the NHS.
It is anticipated that the proposed changes will be implemented in a phased
manner from April 2013.
http://mediacentre.dh.gov.uk/2012/01/25/genomic-innovation-will-better-target-treatment/
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Introduction
2.1
Improving Outcomes: A Strategy for Cancer, published in January 2011, made
the commitment that the Department of Health would develop a
commissioning and funding structure to enable the efficient delivery of high
quality molecular testing of cancers. In January 2012, the Secretary of State
for Health confirmed the commitment to take forward these plans led by the
NHS Commissioning Board.
2.2
Developing a coherent national structure will enable new tests to be
introduced quickly and ensure that all appropriate patients have access to the
high quality tests that can indicate which treatment is best for them.
2.3
This document sets out proposals for the commissioning and delivery of
complex molecular tests for solid and haematological cancers in England. It
has been developed following a workshop held in June 2011 with key
stakeholders (Annex A), an industry roundtable held in March 2012, and in
close association with Cancer Research UK, who are leading major research
in this area. It has also been developed within the context of the changes
introduced by the Health and Social Care Act 2012.
2.4
This document makes proposals for a national approach to molecular testing
in the following areas:






identification of new tests
evaluation of new tests
ensuring patient access to tests
commissioning the tests
delivery of testing service
monitoring of quality requirements and outcomes
To ensure that this approach is effectively implemented, the document also
makes proposals for a programme delivery structure and associated
governance arrangements.
2.5
This document proposes a structure to address the immediate need for
molecular diagnostic tests in England. The Human Genomics Strategy Group
(HGSG) has recommended a long-term strategy for the adoption of genomic
technology into the NHS. We are supportive of these recommendations and
the steering group will work with the HGSG to develop the proposed structure
in line with the future vision for genomic medicine.
2.6
These proposals apply to the NHS in England only. The Scottish Molecular
Pathology Review group has recommended similar structures for Scotland.
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Germline DNA testing to assess a person’s inherited genetic make-up to
predict likelihood of future disease, including testing for future risk of cancer is
already delivered effectively by regional genetics laboratories working together
as the UK Genetic Testing Network (UKGTN) Members of the UKGTN are
required to provide assurance of quality, and scientific validity. Many of
UKGTN members will also provide the types of testing covered by this report
and it is important that the proposed standards are complementary to existing
standards maintained by the UKGTN.
Background
2.8
Cancer is characterised by acquired changes in DNA sequences (mutations)
occurring primarily as a result of cells dividing repeatedly during life. These
genetic or “molecular” mutations can affect how well a particular treatment
works in a patient. For example, the presence of a KRAS mutation in
colorectal cancer makes it unlikely that a patient will benefit from treatment
with antibodies directed at the EGF receptor (EGFR). New treatments are also
being developed that target cellular pathways characterised by particular
mutations.
2.9
Molecular testing can be used to test tumours for specific mutations that
identify cancer patients who are likely to benefit from particular treatments.
This has two major benefits:


those patients who are extremely unlikely to benefit from a specific
treatment can be identified and spared from taking the drug and any
associated toxicity (side effects)
patients who are likely to benefit from an approved drug can be given that
drug right away, improving both the outcomes for those patients and the
cost effectiveness of their treatment.
Molecular testing can also be used to monitor disease activity, to help with
disease diagnosis or in assessing likely disease prognosis (i.e. predicting the
outcome of the disease).
2.10
Molecular testing can take the form of the following type of tests:



immunohistochemistry (IHC): determining the presence of proteins in a
sample. For example, IHC is commonly used to test for excessive levels of
HER2 protein in breast cancer patients, in order to identify patients who
might benefit from trastuzumab (Herceptin, Genetech/Roche)
cytogenetics: examining the shape and structure of chromosomes in order
to detect abnormalities, such as the presence of the Philadelphia
chromosome in chronic myeloid leukaemia
In Situ Hybridisation (ISH): use of probes that bind to particular markers in
DNA. The probes are visualized under the microscope and may be
fluorescent (FISH), coloured/chromogen (CISH) or silver (SISH). For
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example, FISH is used in the diagnosis of soft tissue tumours to highlight
genetic mutations
reverse transcriptase polymerase chain reaction (rt-PCR): used in
combination with FISH, this detects the presence of abnormal gene
products resulting from changes in chromosome structure (e.g.
translocations), for example in soft tissue tumours
DNA sequencing: direct testing of DNA extracted from a tumour sample for
a specific mutation. For example, testing of patients with non-small cell
lung cancer (NSCLC) for the EGFR gene mutation to identify patients who
are most likely to benefit from the drug gefitinib (Iressa, AstraZeneca), or
testing of patients with metastatic colorectal cancer for the KRAS mutation
to identify who are most likely to benefit from the drug cetuximab (Erbitux,
Merck Serono).
Scope
2.11
The proposal in this document relates specifically to DNA, RNA and FISHbased testing of tumour samples, including those from solid cancers and from
haematological cancers.
2.12
Discussions with the community2 have suggested that the priority should be to
focus on DNA, RNA and FISH testing. However, in the long term it would be
useful to have a structure that incorporates IHC and cytogenetic testing. This
is because these tests may be used as part of the testing pathway to identify a
sub-population for genetic testing. For example, one approach to testing
NSCLC patients for ALK translocations is to pre-screen for the presence of the
protein with IHC and confirm the genetic mutation with FISH. This also reflects
the current practice for HER2 testing in breast cancer.
2.13
The scope also excludes testing to assess a person’s underlying inherited
genetic make-up to predict likelihood of future disease, and testing individuals
without cancer symptoms to identify cancer earlier (see Annex B).
Q1. Is the scope of testing covered by these proposals correct and the
exclusions appropriate?
2.14
2
Testing of samples from haematological malignancies is well established and
has predominantly focused on helping with disease diagnosis and prognosis
and in some cases, for identification of patients for particular treatments.
There is currently no evidence of unmet need but haematological
malignancies are included in the scope of these proposals, to address issues
relating to the clarity of funding routes and low volume testing and quality.
There is also considerable overlap in the technology required and, in some
Feedback from the Cancer Research UK Stratified Medicine Programme Study Management Group
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cases, drugs may target both solid cancers and haematological cancers
(imatinib is used for treatment of both chronic myeloid leukaemia and
gastrointestinal stromal tumours). Integrating solid and haematological
cancers into the same system would ensure providers meet the same
performance standards, allow for potential economies of scale and maintain
similar criteria on approving new tests.
Q2. Should the proposed approach include testing for both solid and
haematological cancers?
Current activity
2.15
A list of targeted treatments and associated markers that are tested for in solid
and haematological cancers is outlined in Annex C. Some of the
haematological tests have been in use for at least 15 years and the NHS has
incorporated them into routine care. In contrast, EGFR and KRAS tests (in
combination with specific treatments) were only approved by NICE for use in
the NHS within the last five years. The following section outlines testing
activity for the main molecular tests and focuses on KRAS and EGFR activity
as issues with their rollout into routine care illustrate gaps in the current
structure.
2.16
Cancer Research UK undertook a laboratory survey to identify levels of
complex molecular testing activity in solid tumours and haematological
cancers in the financial year 2010-2011. It was restricted to testing for genetic
mutations in solid tumours and a range of other complex molecular tests for
cancers of blood, bone marrow and lymph nodes (the survey methods and
results are attached in annex D). IHC testing was not included and
information about HER2 testing was restricted to ISH tests using DNA-based
methods.
2.17
The survey identified that approximately 96,000 molecular tests for cancer
(within the above scope) were undertaken in England3 during 2010-2011.
Testing is being undertaken in approximately 40 specialist facilities including
research, clinical and private laboratories. The majority (76%)4 of these tests
were for haematological cancers, which includes tests that are repeated
regularly on patients to track disease progress.
2.18
Demand for testing has been increasing dramatically in recent years (see
figure 1) with the introduction and rollout of new molecular tests such as
EGFR and KRAS. For example, the Royal Marsden Hospital’s Molecular
3
This data was gathered from a survey of genetic testing labs in England to which 38 laboratories responded.
The results and methodology are outlined in Annex D.
4The use of serial testing to track disease progression over time may explain why the figures for haematological
testing are much higher than the number of tests required for solid tumours.
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Diagnostic Laboratory saw a five-fold increase in testing volumes between
2006 and 20105 and the programme of EGFR testing funded by Astra Zeneca
went from zero to over 600 tests per month in just one year (Aug 09-Jul 10 –
figure 2)6.
Figure 1: Increase in NHS testing activity in the Molecular Diagnostics Laboratory (ICR/RMH) per
year from 2006-20107
Figure 2: Total number of EGFR tests reported by Astra Zeneca funded testing centres (columns, left
hand axis), and turnaround times, by month (blue line, right hand axis)
5
Source Royal Marsden Hospital/Institute of Cancer Research via the Stratified Medicine Technology Advisory
Group
6 Source: 12 months experience of EGFR testing in the UK, R. Butler, AstraZeneca et al, 2010
7
2011 data included figures for the Cancer Research UK Stratified Medicine Programme and data was adjusted
to remove these.
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2.19
The demand for this type of testing is likely to increase over the next few years
and it is almost certain that new targeted drugs will be developed for the
benefit of specific subgroups of patients. For example, the anticipated
introduction of the drugs vemurafenib (Zelboraf, Roche)8 for BRAF-mutated
melanomas in 2012 and crizotinib (Xalkori, Pfizer) for ALK-translocated
NSCLCs in 2013 are likely to lead to a need for an additional c.9,500 tests
over the next 2-3 years (see Annex E for calculations). A 2012 review9
indicated a range of molecular targeted drugs are gaining approval with many
others in preclinical and clinical development. This is highlighted in a report on
the oncology market by Oliver Wyman10 that suggested at least 156 new
molecular agents11 with potential for use in cancer treatment are in clinical
development.
2.20
The technology used in testing tumours is also advancing rapidly with
predictions that the cost of sequencing a whole genome will fall below $1000
by 201312, increasing the likelihood of identifying new molecular targets for
drug treatments.
Current commissioning for molecular tests
2.21
Molecular tests are currently funded in the following ways:




2.22
by commissioners as part of the procedure tariff, i.e. as an integrated part
of the acute service contract
by commissioners directly either as a cost per test or block of tests from
the local provider, if mandated by either national guidance or local
business case agreement to fund separately
by commissioners directly either as a cost per test or in exceptional cases
a block contract, from a specialist testing centre (either NHS or private) if
agreed to fund separately
by individual laboratories as part of research projects.
Unless recommended by NICE, local commissioners would expect the Trust to
find the cost for tests internally, or make a business case. Feedback from
commissioners and clinicians has indicated that EGFR and KRAS tests
currently have no specific funding stream outside of normal HRG/ tariff price
paid for diagnosis/ treatment of specific cancers at secondary/ tertiary level. In
some areas local business cases have been approved but in other areas
clinicians are also relying on good will from laboratories to do these tests
8
Received EMA approval March 2012 and therefore could be obtained by the Cancer Drugs Fund
Exploiting the Cancer Genome: Strategies for the Discovery and Clinical Development of Targeted Molecular
Therapeutics. Yap.T.A, Workman.P. Annu. Rev.Pharmacol. Toxicol. 2012. 52:549-73
10 Global management consultancy firm www.oliverwyman.com
11 Dual-Novel Combinations: A new approach to competing in the oncology market place. Oliver Wyman report
2011
12 http://www.nature.com/nbt/journal/v30/n2/full/nbt0212-126a.html
9
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without payment, or as part of a research project (this is more applicable to
new tests such as BRAF testing for the drug vemurafenib)
2.23
This variation in commissioning means a variation in funding. Some patients
will have their tests specifically funded by PCTs, where others will not have a
direct funding route. In hospitals or laboratories where they have been able to
reallocate funds internally, this has allowed patients to receive the tests
required. However, this informal reallocation is vulnerable to the overall budget
constraints that the NHS is experiencing, as well as to the increase in demand
for these tests. If there are no specific budgets in place as new tests are
introduced, there is a risk that new tests may not be fundable and deliverable
by some trusts, leading to inequities in services, treatments and outcomes.
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The Case for Change
3.1
To ensure that all appropriate patients can benefit from targeted treatments as
soon as they are available, it is essential to have equal access across the
country to high quality, accurate molecular testing of tumour samples.
3.2
Whilst molecular testing is already being undertaken in the NHS and private
sector, the absence of a nationally agreed evaluation and quality assurance
process, and variation in commissioning and funding of tests have led to the
slow uptake of new tests, fragmented provision and issues in ensuring
consistent quality of the tests provided13.
Patient access to tests
3.3
Cancer Research UK assessed the number of EGFR and KRAS tests needed
to meet the clinical need in 2010-2011 (see table 3.1 below). This was
compared to a number of EGFR and KRAS tests performed in 2010-2011
which was calculated from data of 2010-11 levels of testing activity identified
from the survey (see Annex D for methodology), and estimates received from
AstraZeneca. This illustrates that for EGFR testing, insufficient tests are being
delivered to meet clinical need. For KRAS testing, there is a lack of consensus
on the appropriate patient populations that need testing and it is unclear if
patients are getting the appropriate tests.
Tumour type
Gene
mutation
Associated
drug
treatment
Number of
tests
performed
2010-2011
Number of
patients
requiring
test p/annum
Estimated
unmet need
(tests p/annum)
Non-small cell
lung cancer
EGFR
Gefitinib
7,300
12,500
c. 5,000
(+/- 10%)
(+/- 20%)
Colorectal
cancer
KRAS
4,38014
0 – c8,600
(+/- 5%)
3,525 –
12,800
Less than
500
7,500
8,000
None
(+/- 5%)
Gastrointestinal KIT and
PDGFRA
tumour
Breast cancer
Cetuximab
HER2
Imatinib
Herceptin
465
Uncertain15
(+/- 20%)
Table 3.1: Estimate of the unmet clinical need for the four main molecular tests in solid
tumours
13
UK NEQAS external quality assessment pilot schemes for molecular genetic analysis of EGFR and KRAS,
Zandra Deans et al, AstraZeneca et al, 2010
14
The amount of KRAS tests delivered was surveyed prior to the revised guidelines from NICE in March 2012
that restricted cetuximab to the first line indication, for use in patients with isolated inoperable liver metastases in
an attempt to render them amenable to surgery. Previous guidance during 2010-2011 had approved use in
second and third line indications for patients who had progressed through other standard therapies.
15 A mix of diagnostic and predictive testing performed and current imatinib guidelines do not stipulate
requirement for testing
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The clinical need for tests is also constantly evolving due to decisions by NICE
and the clinical community on which patient populations should be tested
based on updated evidence. Since the data on KRAS testing (in table 3.1)
was calculated, NICE have revised their guidelines (March 2012) to restrict
cetuximab to a first line indication, for use in patients with isolated inoperable
liver metastases in order to render them potentially operable16. This reduces
the lower estimate of patients requiring tests from 3,525 to 2,300. The clinical
need for testing may also increase in the future, if clinical practice evolves to
incorporate repeat testing for patients with relapsed or recurrent disease.
Q3. Do the figures in table 3.1 accurately reflect the current level of testing
and predicted need for the genes listed?
Q4. Is there evidence of causes of unmet need other than those described
in this paper?
KRAS tests
3.5
Cetuximab is approved by NICE for the treatment of patients with metastatic
colorectal cancer that do not test positive for KRAS mutations (“wild type”).
Two options are shown in the following graph (figure 3) for the predicted
clinical need for KRAS mutation testing. These are dependent on when the
testing is performed in the patient pathway. One option is for KRAS testing at
diagnosis of metastatic disease. This fits into the clinical pathway for sample
testing at diagnosis, and avoids a delay in cetuximab therapy if it is indicated
later in the patient’s disease according to NICE guidance. The second option
is for KRAS testing only when the patient becomes eligible for cetuximab,
which is recommended by NICE for a subset of all patients with metastatic
disease. This second option gives a potential cost saving due to limiting tests
to those who will have an immediate clinical decision made based on the test
result. These options are currently in debate amongst the clinical community
(see Annex F for further information).
Q5. Should NICE define the point in the treatment pathway where
molecular tests should be undertaken?
16
Previous guidance had included use in second and third line patients who had progressed through other
standard therapies
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Figure 3:
3.6
This is also demonstrated in treatment of patients with advanced
gastrointestinal stromal tumour, since there are no clear guidelines on whether
patients should be tested for KIT mutations in advance of therapy and there is
only one licensed targeted drug in England (imatinib, Glivec, Novartis).
EGFR tests
3.7
Gefitinib is approved by NICE for the first-line treatment of patients
with EGFR-mutation positive NSCLC. The approval is largely based on data
from the Iressa Pan-Asia Study (IPASS) demonstrating that in a sub-group of
EGFR-mutation positive patients, gefitinib therapy led to an increase of 3.2
months in the median progression-free survival when compared with standard
paclitaxel and carboplatin chemotherapy17. Figure 4 below illustrates the gap
between the predicted number of EGFR tests that should be happening in
NSCLC patients, and the number that are being tested. This suggests that
c.5,000 NSCLC patients each year are not having their tumour tested for
suitability for EGFR inhibitor drugs. Of the 5,000 patients that should be tested
for EGFR status, c.750 patients18 may be eligible for consideration of gefitinib
therapy with the associated potential therapeutic benefits.
17
Research is still ongoing to establish the overall survival benefits for gefitinib and there is still uncertainty on
how much overall survival is gained by patients.
18Based on assumption approximately 15% NSCLC patients have the EGFR marker: there is no data on
incidence of the marker in a UK population and observations range from 15-25%
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Figure 4:
3.8
There are a number of possible reasons for the unmet need shown for EGFR
tests. Clinicians may not be requesting the tests, the tests may be unavailable,
or there could be funding issues. Discussions with the clinical and
commissioning community suggest that clinicians are requesting tests for
patients but there are no formal national mechanisms for paying for the tests
leading to variations in whether PCTs approve payment for them locally and in
which group of patients funding is provided. For example, unconfirmed internal
survey data from AstraZeneca suggested that specific funding for all patients
eligible for EGFR testing is only found in 12% of NHS Trusts in England,
Wales and Northern Ireland, with the others funding only for a subset of
patients (74%) or not specifically funding EGFR testing (14%). 19
3.9
It is also possible that this gap could reflect patients who are so ill at
presentation that it is not appropriate for them to have treatment, therefore
clinicians do not request the tests. We have tried to account for this in our
calculations through consultation with a number of oncologists, pathologists
and key opinion leaders.
Haematological cancers
3.10
19
It is uncertain whether there is a gap in the provision of molecular testing for
haematological cancers. This has been embedded into routine care for much
longer (approximately 15-20 years) and there has been a move towards an
Source AstraZeneca sales force survey
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integrated molecular pathology service delivered to large populations.
However, similarly to solid tumours, there are no clear commissioning routes
and access is regionally variable.
Consistency and reliability of testing
3.11
High quality, accurate testing is vital to ensure the right patient populations are
identified and prescribed for treatment. Incorrect test results may mean some
patients will not be given treatments when they are eligible, whilst other
patients will be incorrectly given treatments that may not work on them. Data
published from the UK National External Quality Assurance Service (UK
NEQAS) pilot external quality assurance (EQA) schemes for EGFR and KRAS
in 2010-2011 showed incorrect reporting of mutations and errors10, and
variability in how tests were reported. Possible explanations for variability in
the quality of testing include:



low volume of testing in laboratories, delaying the development of
specialist expertise or clinical experience,
lack of participation in external quality assurance schemes so
laboratories do not receive support and feedback to improve service
no formal monitoring and management of quality so technical issues with
tests are less likely to be identified.
Similar issues in test consistency and reliability have previously been identified
in haematological testing services resulting in formal external quality
assurance schemes being developed with NEQAS.
Q6. Do you agree there is an issue with the quality of testing and for the
reasons stated above?
Quality of sample processing
3.12
Specimen handling processes in histopathology laboratories are key in
determining tissue quality for testing. The histopathology laboratory is
responsible for specimen receipt, identification, fixation (preservation of tissue
using formalin), dissection, processing, paraffin block and slide preparation
and storage, and report and data archiving. All these processes are essential
for ensuring that the right test is done on the right specimen to make the right
diagnosis. For molecular testing, the histopathology department is additionally
responsible for retrieving, preparing and arranging for transport of tumour
samples to specialist testing centres as well as providing the relevant
identifiers and clinical information. A tissue sample that has been incorrectly
processed at any stage may render it unusable for testing.
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Costs of this work tend to be absorbed by the histopathology
laboratories/trusts concerned. National quality and productivity initiatives have
led to a significant ongoing programme of reform of pathology services,
including budgetary targets. In this context, informally funded work is
particularly vulnerable. There is a risk that without recognition of the additional
costs and some form of reimbursement, this work may become unsustainable
or not adequately prioritised. Therefore, samples may not be prepared
correctly, to sufficient quality or within timeframes needed to meet clinically
relevant turnaround times.
Timely roll out of new tests.
3.14
The adoption of new tests in solid tumours has largely been driven by
partnerships with pharmaceutical companies funding tests in advance of NICE
approval of the associated drug treatment, to create the necessary
infrastructure for the tests20.
3.15
Despite funding initiatives like this, uptake is generally slow and locally
variable. For example, during AstraZeneca’s investment to fund EGFR testing,
it took a year to reach the present rate of testing21. This meant that during the
first year, some patients who should have got the test were missing out while
the service was being built up in their area. Even now, not enough patients are
being tested. Similarly, despite the significant investment made by Roche in
rolling out HER2 testing capacity throughout the NHS from 2005-2007 to
support the rapid identification of patients eligible for treatment with Herceptin,
there remained considerable variation in the speed of adoption across the
country. The following map22 (figure 5) shows the variations in testing policies
and rates between different cancer networks in 2006.
20
AstraZeneca UK funded EGFR gene testing for a period of 15 months from July 2009 to the end of October
2010. In 2011, Merck announced funding for KRAS testing for all colorectal cancer patients at the point of
diagnosis.
21 Twelve months’ experience of EGFR mutation testing in the UK R. Butler, Head of All Wales Molecular
Genetics Laboratory, Cardiff and Vale University Health Board; A. Williams, Medical Affairs Scientist,
AstraZeneca UK; G. Walker, Medical Affairs Advisor, AstraZeneca UK;N. Marsh, Medical Science Liaison,
AstraZeneca UK
22
Data provided by Roche
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Figure 5
3.16
For haematological cancers, the drive to roll out new tests has predominantly
been by local clinical-academic interest.
3.17
There is also currently no nationally agreed process for determining what tests
should be undertaken, and on which patient groups, resulting in regional
variation in practice. This is demonstrated by the different views in the
colorectal clinical community about what point in the patient pathway patients
should be tested for KRAS mutations.
3.18
With the likelihood of targeted treatments and associated tests increasing,
testing services need to be capable of implementing new tests quickly with
guidelines on patient eligibility and test quality.
Building partnerships with industry
3.19
Pharmaceutical companies have taken a role in facilitating the adoption of new
tests. This has been through funding tests after their associated drug
treatment has received their license from the European Medicines Agency, but
prior to NICE approval. The drugs are often funded through the Cancer Drugs
Fund or other means, and these benefit patients by providing early access to
new treatments.
3.20
Lessons can be learned from the experiences of these companies in rolling
out nation-wide diagnostic testing programmes in cancer. For example, Roche
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manufactured Herceptin (trastuzumab), the first treatment targeted at cancer
patients with a particular biological characteristic, and provided support for
rollout of Her2 testing. They have also recently helped to fund the testing
infrastructure to support the launch of Zelboraf (vemurafenib) for metastatic
melanoma, which targets the mutated cancer-causing protein B-RAF. The key
challenges they identified in rolling out these tests focused on variations in the
quality and availability of testing, including:





3.21
multiple testing platforms and approaches to interpretation
inconsistency of test results on the same platform
a lack of agreed protocols and testing pathways
differences in the quality, capacity and turnaround times of laboratories
variances in the referral rates of patients and testing policies across
cancer networks.
Discussions with industry have indicated a willingness to continue this type of
partnership with the NHS, although the value of this approach is dependent on
the proportion of patients who require the test vs. those who will require the
drug. Companies have indicated they would prefer a standardised approach to
how this type of funding would work and an important aspect will be to ensure
that tests are completed to standards in line with those required by
commissioners and regulatory authorities. It is recommended that the steering
group work with industry and commissioners to facilitate this approach.
Improving research capacity
3.22
A national approach to molecular diagnostic testing could enable research
through:


Incorporation of routine generic consent into patient pathways enabling
researcher access to tissue samples and clinical data
Standardised data and linkage of molecular and clinical data enabling
researchers and research funders to identify cohorts of patients and
further analysis of data contributing to knowledge about the interaction
between genes and disease progression (See paragraphs 4.33-4.36 for
further information).
Cost / benefits analysis
3.22
There are complex questions around the long-term systemic financial impact
of molecular pathology through reducing the use of ineffective treatments,
which are out of the scope of this report. The NHS will answer these questions
through the HGSG’s recommendations to commission a genomics health
economic analysis.
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3.23
The single technology appraisal process used by NICE to assess the cost/
benefit of new cancer drugs includes the costs of any molecular testing
required as part of the treatment. The costs of any specific tests are taken into
account together with the other elements of additional costs from the proposed
new treatment and savings from discontinuing any alternative interventions.
3.24
A proposed new treatment that meets the cost/benefit threshold does not
imply overall cost savings. For example if the benefit of a new drug treatment
is mainly from increased QALYs (e.g. an increase in progress-free survival)
then the new treatment may require additional funding to achieve the
improved outcome.
3.25
The Strategy23 published in January 2011 outlined a range of actions to
improve care and reduce death rates for cancer patients. The actions
identified in the Strategy were estimated to require an increase in the spend
on cancer care by over £500m/ year by 2015-16. The strategy recognised that
the increase in availability of anti-cancer drugs therapy has created cost and
capacity pressures for the NHS given that new drugs are often used in
addition to surgery and radiotherapy, as well as existing forms of cancer
drugs. The strategy included the aim to offset the cost pressures of drugs for
advanced or metastatic cancers by increasing the proportion of patients
treated at an earlier stage of the disease.
3.26
Typically, the cost of molecular testing is around a tenth of the direct cost of
the drug for which it is being used24. This includes the cost of tests on patients
for which the drug is not suitable. The lower proportion of patients for which
the treatment is indicated, the higher the diagnostic cost per patient will benefit
from the treatment. For the conditions where there are a relatively low number
of potential patients suitable for treatment indicated by molecular testing
(typically less than 20%) then the testing cost can be significant in the cost
benefit analysis25. Small differences in the proportion of patients can tip the
balance between if the overall assessment is if the cost /benefit meeting the
threshold value or not. So although the costs of individual tests may seem
modest compared to the whole programme of treatment they can become very
important in the cases where the treatment is close to the cost benefit
threshold.
3.27 From the evidence presented earlier in this consultation an estimate has been
made of the cost and volume of four of the molecular tests, summarised in
table 3.2.
23
The Improving Outcomes: A Strategy for Cancer, DH, January 2011
http://www.nice.org.uk/nicemedia/live/11918/44413/44413.pdf
25 http://www.nice.org.uk/nicemedia/live/12185/48834/48834.pdf
24
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Tumour Site
Molecular
test
Associated
treatment
Tests
2010/11
Upper
estimate
of total
demand
Cost per
test
(£
estimate)
Total cost
(£millions)
of upper
estimate of
demand
NSCL
EGFR
Gefitinib
7,300
12,500
150
1.9
Colorectal Cancer
KRAS
KIT &
PDGFRA
Cetuximab
4,380
12,800
145
1.9
Imatinib
465
500
145
0.1
HER2
Herceptin
7,500
8,000
146
TOTAL
1.2
5.0
Gastrointestinal
stromal tumour
Breast Cancer
Table 3.2 Estimate of the molecular test volume and cost of four main cancer types
3.28
Extra funds will be required to run the administration of the process of the
proposed new structure for cancer molecular pathology that will be
commissioned via the NHS commissioning board and be overseen by a
steering group. This may involve:



ongoing costs of running the steering group
ongoing cost of running the topic selection for new tests
cost of 1-4 commissioners – depending on the structure.
This process in addition to quality and clinical prioritisation will be required to
demonstrate that testing achieves good value for money, including any new
tests as and when they are required.
Q7. Do the volume and cost estimates in table 3.2 seem reasonable as a
starting position for use in planning assumptions?
Q8. What level of resource do you estimate would be needed to ensure,
quality, value for money and the timely introduction of new tests under
the new commissioning arrangements?
Q9. Will the costs of the current tests be a good indication of the costs of the
next wave of tests?
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Proposed approach
4.1
The proposed approach to testing makes recommendations in the following
areas:






identification of new tests
evaluation of new tests
patient access to tests
commissioning the tests
delivery of testing service, and
monitoring of quality requirements.
To ensure that this approach is effectively implemented, the programme
delivery structure and associated governance arrangements should be
overseen by a steering group. The following diagram (figure 6) outlines this
approach and detailed descriptions of each area are contained in the following
sections.
Figure 6:
Cancer molecular pathology – proposed structure and fit to
existing and new groups
National Horizon Scanning Centre
Royal College Pathologists
Clinical Molecular Genetics Society
NCRI Clinical Study Groups
Topic
identification
Group
Existing group
New group
NICE Medical
Technology
Advisory
Programme
NICE Diagnostics
Oversight by
Steering
Group
UK NEQAS
NHS
Commissioning
Board
Cancer Registry
and NCIN
Quality assurance
NHS, academic
and private labs
Test and
clinical
results
Patients
Q.10
Referring
Hospitals
Is the proposed structure both comprehensive and appropriate?
Identification of new tests/topic selection
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New tests should be assessed for use in the NHS in a timely fashion. New
molecular tests can be developed either by commercial diagnostic companies
or by NHS/ academic laboratories for use in NHS diagnostic laboratories. New
tests can be identified for the following purposes:



to predict response to a new targeted treatment
to predict benefit (or not) from an existing drug
to give clinically useful prognostic information about the cancer and its
progression e.g. minimum residual disease monitoring in leukaemia.
4.3
NICE has an established means of identifying diagnostic technologies for
evaluation involving notifications from sponsors, who may be commercial,
clinical or those working in academic research settings. In practice, most of
the tests evaluated by NICE so far have come from commercial sources.
Potential topics are considered by the Medical Technologies Advisory
Committee (MTAC), who also identify which programme at NICE is most
appropriate to consider the product. Diagnostics that have a value proposition
based on a higher cost and more benefit and/ or a complex diagnostic or
treatment pathway are normally scoped and evaluated by the Diagnostic
Assessment Programme (DAP). A Medical Technologies Topic Oversight
Group is responsible for the MTAC, reviewing their decisions and any issues
that arise during the scoping process.
4.4
There is currently no routine mechanism for proposal to NICE of eligible topics
that do not have a commercial sponsor. Possible non-commercial sources for
these suggested NICE DAP topics include academic researchers, published
scientific research, the National Clinical Directors (particularly for Cancer and
Pathology), the Royal College of Pathology National Laboratory Medicines
Catalogue, research funding bodies and NCRI Clinical Studies Groups.
4.5
A small Topic Identification Group should be established to bring together
intelligence from these sources and consider the utility of NICE or another
body evaluating proposed topics. This group will seek input from the NCRI
Clinical Study Groups, the Clinical Molecular Genetics Society, the Royal
College of Pathologists Inter-Specialty Committee on Molecular Pathology and
the National Horizon Scanning Centre. It will be chaired by a representative
from NICE DAP and will include a representative from the NICE Centre for
Technology Evaluation and the Royal College of Pathologists. This topic
identification could be effective from autumn 2012.
4.6
The National Horizon Scanning Centre has existing capability to keep these
sources under surveillance and could be responsible for submitting suitable
tests and evidence for review to the Topic Identification Group.
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Q11. Will this approach enable the timely identification of new tests?
Q12. How much of this process/ structure should be formal?
4.7
Based on current resource levels, approximately five topics identified in this
way could be reviewed by NICE DAP each year. This rate of reviewing is
considered sufficient to assess new tests, at the current pace of new test
development.
Evaluation of new tests
4.8
The NICE DAP should take the lead on assessing new molecular tests for
cancer. Tests with likely additional net cost and a claim of improved benefit
and/ or performance will normally be eligible. Currently tests that are
assessed are required to have CE marking but the DAP is considering how to
select and assess non-CE marked tests, which are common in NHS practice.
4.9
The NICE DAP should be asked to consider:



advising on technological advances related to mutational analysis
(irrespective of target)
assessing specific new molecular tests – and the patient groups who will
require testing
assessing combinations of molecular tests, when appropriate.
Greater clarity will be required on what analytical and clinical validity is
required to establish the cost effectiveness of new molecular tests and it is
expected that this will be provided by NICE DAP.
4.10
It is important for NICE DAP to provide clear guidelines on what patient
populations should be tested, and at which part of the patient pathway they
should be tested. The point at which testing is appropriate will need to be
based on both clinical justification and cost effectiveness. For example,
suggestions from pathologists to Merck Serono have indicated that if the rate
of KRAS testing goes above 10% it may be cheaper to test all patients at
diagnosis rather than retrieve the diagnostic blocks at a later date. It will also
be important to provide recommendations on what type of testing approach
should be used. For example, identification of NSCLC with ALK gene
translocations can be performed using IHC, FISH, rt-PCR or a combination of
these methods.
4.11
There may be some cases where there is less economic incentive to gather
sufficient clinical and analytic data to establish the cost effectiveness of a test
e.g. to stratify patients out of existing treatments. In these cases, it may be
necessary to explore the use of existing NHS R&D and NIHR funds to support
the necessary data collection.
23
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Where an assessment of a molecular test relates specifically to a new drug
also being appraised by NICE, the assessment and guidance to
commissioners would form part of the NICE Technology Appraisal Guidance.
They will make recommendations on the new drug based on the test licensed
for use with it (normally, this would also be the test used in the clinical trials
considered in the appraisal). Where a molecular test is being assessed
separately from a technology appraisal, it would be evaluated by NICE DAP
and recommendations would appear in NICE Diagnostic Guidance. In some
cases, there may be multiple companion diagnostic options to support the use
of NICE approved drugs. These options may include multiple proprietary CE
marked diagnostics and “in-house” tests. The evaluation of such multiple
companion diagnostic options would be undertaken by NICE DAP.
Commissioning of molecular cancer testing
4.13
Given the rapid developments in the field of molecular testing for cancer and
the close linkage to the introduction of costly new treatments, effective
commissioning for molecular testing will require specialist knowledge of testing
processes and a governance structure that would enable monitoring of
providers to maintain a high quality and cost effective service. The proposed
operating model for the NHSCB will ensure that all criteria for establishing new
tests are nationally agreed and that until a new test is well established with
clear guidelines on suitable patient populations there will be nationally agreed
governance arrangements to ensure that the tests are targeted at the right
patients. Central coordination will also enable close working with NICE to
make timely decisions to facilitate parallel approval of tests and drugs (where
this is appropriate within licensing arrangements) and enable interactions with
the Cancer Drugs Fund and the pharmaceutical and diagnostic industries.
4.14
It is our intention that commissioning for molecular testing will be undertaken
by the NHS Commissioning Board alongside other prescribed services. Once
a test or technology has demonstrated its clinical validity and utility and been
recommended by NICE or another relevant authority, it will be nationally
commissioned from providers.
4.15
There are currently no national tariffs set for molecular tests and local prices
may be used. It is likely that in the long-term tariff based pricing will be
established (a minimum of three years is required to develop these). National
tariffs are normally based on data collected from NHS Trusts, which would
require specific codes set by the Health and Social Care Information Centre.
The UK GTN/ Clinical Molecular Genetics Society have devised a
methodology to record laboratory activity consistently and that is being used in
molecular genetics laboratories to record activity of testing for inherited
genetics disorders. This methodology could be applied to measure the activity
of cancer genetic tests to help develop tariffs.
24
Molecular diagnostic testing
4.16
consultation
draft v3.8 26 April 2012
Commissioners will need to set quality requirements to ensure that the testing
delivered is high quality, cost effective and fits into patient care pathways.
Some initial recommendations are outlined in the section on delivery of
molecular testing and advice will be provided by the steering group.
Patient Access
4.17
Currently, tests are predominantly requested by oncologists through
histopathologists and discussions at cancer multidisciplinary team (MDT)
meetings within the hospitals. As these tests become routine, and depending
on the point at which they are requested in the patient pathway, this
responsibility may transfer to pathologists.
4.18
It is not clear whether any of the gaps in testing provision might be due to tests
not being requested. As demonstrated by KRAS and KIT testing, clear
guidelines are needed to identify which patients are eligible for molecular tests
and this should be provided as part of NICE guidance. It will important to
monitor regional uptake of these tests to identify if gaps persist.
Delivery of molecular testing
4.19
There is widespread consensus that testing should be carried out in specialist
centres with clinical experience and expertise. This approach is also in line
with conclusions from the recent Human Genomics Strategy Group report26.
This type of approach has also been used in molecular testing in
haematological cancers27.
4.20
Consideration has been given to the optimum number of specialist centres
required in England to deliver molecular testing but no consensus has been
reached28. Rather than designating a fixed number of sites, it is recommended
that commissioners should set rigorous value and quality requirements that
are monitored and continuously improving (e.g. test consistency, turnaround
time). These standards should ensure that molecular testing is undertaken in
laboratories that can:



introduce new tests and technologies quickly once they have been
deemed to be clinically useful and cost-effective
deliver testing to a high quality in terms of reliability and reproducibility
undertake a sufficient number of tests each year to retain expertise and
an auditable volume of testing. This will be particularly important with
advances in next generation sequencing and genomics leading to
complex, high-cost and high-throughput equipment. In some cases, if a
26
Building on our inheritance, Genomic technology in healthcare
To improve accuracy/quality of tests and provide economies of scale, NICE Improving Outcomes Guidance
2003 recommended that each Cancer Network used a single integrated service combining histology/cytology,
immunology and cytogenetic/molecular diagnostics that would provide a combined report.
28 At workshop held by the Department of Health in June 2011, suggestions varied between 2 and 30.
27
25
Molecular diagnostic testing




consultation
draft v3.8 26 April 2012
molecular test is developed that has a small patient population,
commissioners may choose to assign activity to a particular provider
deliver testing results within specified turnaround times, so that treatment
decisions are not delayed
participate in external quality assurance process and CPA accreditation.
These requirements have been shown by UKGTN to be successful in
ensuring laboratories are capable of delivering high quality standard in
testing for inherited genetic disease
collect and share a defined dataset for monitoring processes
provide support to research studies.
These quality requirements should be informed by the genetic services
specification and quality dashboards in development by the genetics Clinical
Assurance Group29.
4.21
There are a range of opinions on the minimum number of tests that a lab
should provide in order to be auditable and deliver high quality testing at
appropriate costs. A lung cancer working group recommended “the number of
annual EGFR tests considered optimal for guaranteeing the technical
sufficiency of a laboratory is arbitrarily set at 50”30. Merck Serono’s UK
affiliate, when commissioning KRAS testing from laboratories in the UK, have
required a minimum threshold of 500 tests a year. A French national report on
the economics of haematological molecular testing recommended a threshold
of 1,000 samples per year for pre-analytic work (e.g. DNA extraction) and 500
per year for analytic work (e.g. gene mutation testing).31
Q13.
Is there a recommended threshold, either for a provider or for an
individual test, below which it is not possible to audit quality and value
effectively?
Q14.
Is two to three months a reasonable period of time to set up a new test?
Q15.
Is ten working days from the point of request to the receipt of results by
the clinical team a reasonable turnaround time for tests?
Q16.
Is a ten day turnaround clinically appropriate and are there any types of
tests unlikely to be delivered in this time?
Q17.
Should any other requirements be included for test providers?
29
This is one of fifty-five Clinical Assurance Groups led by clinicians that have been set up to review specialised
service national definition sets.
30
Thunnisse E et al. The challenge of NSCLC diagnosis and predictive analysis on small samples. Practical
approach of a working group. Lung Cancer (2011), doi:10.1016/j.lungcan.2011.10.017
31Évaluation de la structuration et organisation en réseaux régionaux des activités de biologie innovantes en
onco-hématologie, December 2010 InCA, wwe.e-cancer.fr
26
Molecular diagnostic testing
4.22
consultation
draft v3.8 26 April 2012
The haemato-oncology community, in the testing of inherited genetic
diseases, has seen success in improving performance through networks of
providers that come together to advise on standards and resolve issues. It is
recommended that a future Steering Group considers the role of such a
network in providing the updated recommendations on standards to the NHS
Commissioning Board.
Q18.
Should there be a specialised network for molecular diagnostic testing
in cancer or should this be part of a wider molecular based network?
Monitoring of standards
4.23
To ensure a uniform service is delivered nationally and meets the
requirements outlined above, providers will be required to provide specific
data on test quality, activity and turnaround times as part of their service
agreements. It is important to ensure this data is standardised to enable
effective comparisons between providers. We propose that this standard
dataset is initially defined by the Steering Group. Commissioners will then be
responsible for reviewing this data with advice provided by the Steering
Group.
4.24
It will also be important to link testing data to national clinical and outcomes
data such as the chemotherapy dataset, Hospital Episode Statistics (HES),
and cancer registry data. This will enable service audit, tracking of survival
rates in comparison to clinical trials and real world evidence that may help
refine patient populations for testing.
Test and sample quality
4.25
CPA accreditation includes the requirement for laboratories to prove they have
complied with EQA schemes, where laboratories test blinded samples where
the test result is already known and their results are compared with results
from other laboratories. Existing EQA schemes for KRAS, EGFR and KIT
testing are run by the UK NEQAS. Laboratories that are unable to meet the
standards are provided with support to resolve issues and EQA schemes are
run repeatedly in order to monitor performance. Issues with persistent poor
performance or non-resolution of issues are escalated to a Royal College of
Pathologists joint working group with CPA representation.
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4.26
UK NEQAS are currently developing schemes for forthcoming tests such as
BRAF and ALK and the haematological community are developing schemes
with UK NEQAS for their existing tests. UK NEQAS should continue to monitor
quality assurance for cancer molecular testing and CPA accreditation should
be a mandatory standard for any provider. Service providers will be required to
provide data on their EQA performance to the NHS Commissioning Board as
part of their service agreement.
4.27
The quality of samples provided by the local histopathology laboratories to the
testing laboratories directly influences the quality and amount of the DNA that
can be extracted and the subsequent test results. Preparing samples
(especially small biopsy or cytology samples) using methods that maximise
the amount and quality of DNA that can be extracted will become increasingly
important as molecular tests become routine, particularly if samples require
multiple tests. Currently no guidelines exist on how to prepare samples at the
optimum level for maximum DNA extraction and it is recommended that the
Inter Specialty Committee on Molecular Pathology of the Royal College of
Pathologists develop these. Histopathology laboratories’ adherence to these
guidelines will be audited through standard inspections that occur every four
years as part of their clinical pathology accreditation (CPA).
Testing activity and turnaround times
4.28
Providers will be expected to supply data to commissioners on number of tests
performed and turnaround times, as part of the standard dataset. It is
recommended that data be included on the patient’s postcode and which
hospitals referred the tests, as this will enable commissioners to assess if
there are any regional gaps in requesting tests, over prescribing or differing
access between equality groups.
4.29
Regional cancer registries collect data on the incidence, mortality and survival
from cancer. It is recommended that a lead registry be given responsibility for
collecting molecular pathology data from commissioned service providers and
it may be useful to link this to the registry responsible for chemotherapy data.
This will enable the testing data to be linked to treatment and outcomes data.
To enable this, providers should be required to provide data in an electronic
format that can be uploaded into registry systems.
4.30
Further work will be needed to define the dataset but this could be based on
the dataset that Cancer Research UK is piloting with the Eastern Cancer
Registry and Information Centre as part of their Stratified Medicine
Programme. Cancer Research UK intends to submit these data items with
implementation evidence, to the Information Standards Board (ISB) for health
and social care either as an addendum to the Cancer Outcomes and Services
Dataset or a companion standard with final approval anticipated by July 2013.
Links to research
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4.31
Samples taken from patients for use in diagnostic and molecular tests have
significant research value. We propose that patients should be routinely
consented for use for generic use of leftover tissue for non-interventional
research. This research would involve further analysis of the samples, and
comparison to diagnostic and outcomes data to build knowledge about the
interaction between genes and disease progression. In addition, this research
could include screening of large numbers of samples to identify groups of
patients that could chose to join a new targeted trial that aims at a gene fault
present in their samples. Patient data would be anonymised and further
consent would be sought for any research that involved a change their care.
4.32
This directly benefits researchers, both public and private, and research
funders by enabling and speeding up access to valuable research resources.
It does not benefit patients directly in the short term but ultimately it is hoped
that this will lead to better treatments and patient care. This is particularly
important in genetic research where in order to identify the underlying genetic
causes of many conditions, it is helpful to study thousands of genes, or
sections of genetic code, in thousands of patients. This view was supported in
the HGSG report on genomics in healthcare.
4.33
This approach could allow research funders, such as pharmaceutical
companies, government research funders, and charities, to come together and
collaboratively fund broad panel testing for important mutations on a large
number of patient samples. This would make it easier for clinicians to identify
patients, whose specific tumour type means that they would be suitable for a
targeted trial, making it easier, quicker, and more cost effective to run these
trials in England.
4.34
As well as additional tests being done retrospectively on archived samples, we
recognise the scope for additional testing to be delivered within the standard
pathway as a means to build research capacity, and recommend that
commissioners set up structures to enable this.
Q19.
Should we routinely request consent for research on surplus tissue?
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Implementation
5.1
Implementation of the molecular testing programme for cancer should be
overseen by a temporary Steering Group. The group should include the
National Cancer Director, the chair of the NICE Diagnostics Advisory
Committee, the chair of the Inter-speciality Committee on Molecular Pathology
of the Royal College of Pathologists, the chair of the Human Genomics
Strategy Group and representatives from all parts of the pathway including:






5.2
the NHS Commissioning Board
NICE DAP
the clinical/academic community
service providers (NHS and private)
patients
UK NEQAS.
This role of this group will be to:





Q20.
oversee implementation of revised commissioning structure including
resolution and recommendation changes
advise commissioners on testing standards
provide initial support to commissioners on enforcing and monitoring
standards and over/under use of tests.
advise NICE on timing of assessments.
provide links with the wider NHS genomics strategy proposed by the
HGSG.
Are there any significant risks or issues not covered by this report?
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Annex A
Attendees at DH stakeholder meeting for Molecular Diagnostics, 30th June 2011
If you are included in the list below, please can you check your description is correct and
notify us if there are any inaccuracies.
Professor Sir Mike Richards,
Jane Allberry,
Dr Mark Bale,
Dr Graham Bell,
Dr Rachel Butler,
Cheryl Cavanagh,
Mark Cohen,
Dr Trevor Cole,
Mark Dexter,
Jane Deller,
Dr Angela Douglas,
Dr Rob Elles,
Professor Peter Farndon,
Professor Adrienne Flanagan,
Dr David Gonzales-de-Castro,
David Griffiths-Johnson,
James Peach,
Matthew Johnson,
Professor Peter Johnson,
Monica Jones,
Mike Kemp,
Alastair Kent,
Professor Adrian Newland
Dr Caitlin Palframan,
Dr Gavin Roberts,
Alice Tuff,
Richard Wooster,
Tracy Parker,
National Clinical Director for Cancer, Chair
Head of Cancer Policy Team, Department of Health,
Interim Director Genetics, Department of Health,
Lead Technologist, Technology Strategy Board,
Head of Laboratory, All Wales Medical Genetics Service,
Department of Health,
Department of Health,
Chair, Joint Committee on Medical Genetics, RCP
GMC representative,
UK Genetic Testing Network,
Association for Clinical Cytogenetics (ACC),
Head of the National Genetics Reference Laboratory (Manchester),
Director of NHS Genetics Education and Development Centre, Chair
of UK Genetic Testing Network and Professor of Clinical Genetics at
the University of Birmingham,
Centre for Tissue Regeneration Science, UCL,
Institute of Cancer Research & Royal Marsden Hospital,
Department of Business, Innovation and Skills
Director, Stratified Medicine Programme, CRUK
National Specialised Commissioning,
Chief Clinician CRUK,
Stratified Medicine Informatics Lead, Cancer Research UK
Consumer representative,
Director Genetics Alliance UK
National Institute of Health and Clinical Excellence (NICE),
Policy Manager, Breakthrough Breast Cancer,
Economic Adviser, Department of Health,
Stratified Medicine Programme Manager, Cancer Research UK
Vice President and Head of Cancer Metabolism Drug Discovery at
GlaxoSmithKline,
Department of Health
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Annex B
Exclusions from scope
The scope of the document does not include the following:
1. Tests that do not involve DNA/ RNA e.g. protein-based tests such as
immunohistochemistry. Stakeholders have commented that these tests do not
require very specialised or expensive equipment and can be efficiently
delivered through local histopathology labs.
2. Germline DNA testing to assess a person’s underlying inherited genetic makeup to predict likelihood of future disease, including testing for future risk of
cancer (such as BRCA gene testing for breast/ ovarian cancer), This form of
testing is already delivered effectively by regional genetics laboratories
working together as the UK GTN.
3. Molecular testing in asymptomatic individuals to identify markers indicating
cancer at an earlier stage. This promising approach requires further research
before being suitable for implementation in the NHS.
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Annex C
Treatments associated with molecular targets: current and future
A) Current treatments with molecular indications that are EMA approved or under review
Drug
Cancer
Biomarker
indication
Status
Philadelphia
chromosome
positive (Ph+)
CML, Ph+ ALL,
EMA Approved
NICE Approved
Imatinib resistant
Ph+ CML and
Ph+ ALL
EMA Approved
Imatinib resistant
Ph+ CML
EMA Approved
CD-20
EMA Approved
Imatinib
(Gleevec/Glivec)
Vemurafenib
(Zelboraf)
Chronic myeloid
leukaemia,
acute
lymphoblastic
leukaemia
Chromic
myeloid
leukaemia,
acute
lymphoblastic
leukaemia
Chromic
myeloid
leukaemia
B cell nonHodgkin’s
lymphoma
Gastrointestinal
stromal tumour
Malignant
melanoma
KIT (CD117)
EMA Approved
EMA approved
Panitumumab
(Vectibix)
Colorectal
cancer
Crizotinib
(Xalkori)
Lung cancer
Cetuximab
(Erbitux)
Colorectal
cancer
Advanced
melanoma with
BRAF V600E
mutation
EGFR
expressing,
metastatic
colorectal
carcinoma , nonmutated (wildtype) KRAS
Advanced nonsmall cell lung
cancer (NSCLC)
with an ALK gene
translocation
EGFR+
metastatic
colorectal cancer
with wild-type
KRAS, advanced
head/neck cancer
Haematological Imatinib
cancers
(Gleevec/Glivec)
Dasatinib
(Sprycel)
Nilotinib
(Tasigna)
Rituximab
(Mabthera
Solid tumours
EMA Approved
Under review
by EMA
EMA Approved
NICE Approved
for a subset of
patients with
metastatic
colorectal
cancer
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Erlotinib
(Tarceva)
Lung cancer
Gefitinib (Iressa)
Lung cancer
Trastuzumab
(Herceptin)
Breast cancer
draft v3.8 26 April 2012
Advanced
NSCLC (EGFR+
in the EU),
advanced
pancreatic cancer
Advanced
NSCLC (EGFR
mutation positive
in the EU)
HER2+ breast
cancer, advanced
gastric or gastrooesophageal
junction
adenocarcinoma
EMA Approved
EMA Approved
NICE approved
EMA Approved
NICE approved
B) Emerging Cancer Therapeutics – Potential Molecular Tests
Cancer type
Therapy class
Associated
gene test(s)
Drug
Colorectal
EGFR inhibitor
KRAS/BRAF
mutations
IGF1R
mutations
Erlotinib*
IGF1R inhibitor
C-MET inhibitor
MEK inhibitor
mTOR inhibitor
Malignant
melanoma
BRAF inhibitor
MEK inhibitor
c-Kit inhibitor
Phase of
current clinical
trials
III
Dalotuzumab
(MK-0646)
Cixutumumab
(IMC-A12)
II
OSI-906
ARQ-197
I
II
MSC1936369B
Everolimus
(Afinitor)*
I/II
II
BRAF / NRAS
BRAF
mutations
KIT mutations
GSK-2118436
GSK-1120212
III
III
Imatinib
mesylate*
II
EGFR/KRAS
mutation
BRAF
PI3KCA / PTEN
mutations
CML
BCR-ABL inhibitor
BCR / ABL
fusion and
mutations
Bosutinib (SKI606)
III
Pancreatic
IGF1R inhibitor
mTOR Inhibitor
Ganitumab
(AMG-479)
Everolimus*
II
Gastric
Breast
mTOR inhibitor
IGF1R
mutations
PTEN / PIK3CA
/ Akt mutations
PIK3CA / PTEN
Everolimus
III
III
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Molecular diagnostic testing
Cancer type
Therapy class
PARP inhibitor
PI3K inhibitor
NSCLC
EGFR inhibitor
c-Met Inhibitor
IGF1R inhibitor
Ovarian
PARP inhibitor
PARP inhibitor
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draft v3.8 26 April 2012
Associated
gene test(s)
Drug
mutation
(Afinitor)*
Ridaforolimus
Temsirolimus
(CCI-779)
Iniparib
Veliparib (ABT888)
AG-014699
XL-147
BEZ-235
PX-866
BIBW2992 (Tovok,
Afatinib)
ARQ-197
BRCA1 /
BRCA2
mutation
PI3KCA / PTEN
/ Akt mutations
EGFR / KRAS
mutations
EGFR / KRAS
mutations
IGF1R
mutations
MetMAb (RG3638)
Dalotuzumab
(MK-0646)
BRCA1 /
BRCA2
mutations
Iniparib (BSI-201)
EGFR
mutations
Erlotinib*
Phase of
current clinical
trials
II
I/II
III
II
I/II
III
III
II
II
II
III
* Product launched for other indication.
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Annex D
Survey of current testing activity
SURVEY OF SOMATIC CANCER GENETIC TESTING IN ENGLAND 2010-2011
Cancer Research UK carried out a survey of somatic cancer genetic testing in England for
financial year 2010-2011. Data was collected on tests for:
 HER2 in breast cancer (in-situ hybridisation only)
 EGFR in non-small cell lung cancer
 KRAS in colorectal cancer
 KIT in gastrointestinal stromal tumour (GIST)
 cancers of the blood, bone marrow and lymph nodes
 cancers of muscle, bone and soft tissue
 other childhood cancers
 other (including brain tumour and melanoma of the eye)
The aim of the survey was to determine current testing activity data, to allow comparison
with incidence data and identify any unmet need for testing in England.
Data collection and missing labs
Data on the number of tests completed and their approximate cost was requested from all
major molecular and cytogenetics laboratories. This list of laboratories was crosschecked
with membership listings of the Clinical Molecular Genetics Society and UK Genetic Testing
Network. Data was also collected from laboratories within major cancer centres and
laboratories listed as providers of KRAS, EGFR and KIT (for GIST) testing according to the
pharmaceutical companies. Additionally, an advertisement about the survey was placed in
Royal College of Pathologists e-Newsletter November 2011.
Data was submitted by 37 laboratories, either separately for each speciality lab or jointly for
the trust or service. In order to improve the estimation of unmet need for HER2, EGFR,
KRAS and KIT, data from two additional laboratories who did not respond was estimated by
Cancer Research UK. Six laboratories reported that they do not do any of the tests in the
survey.
Data was not made available by a small number of laboratories when requested, largely
due to confidentiality of the data and these omissions will mainly underestimate the number
of tests for cancers of blood, bone marrow and lymph nodes. This is not perceived to be a
significant issue, as this testing is believed to meet current clinical need in these cancers.
This uncertainty is reflected in the “reliability of data” column in the table below.
Results
Laboratory identifiers have been removed due to confidentiality of financial data. All activity
data in the graphs is shown by the laboratory unit as they responded to the survey and
reflects the laboratories’ view of their organisation of their services. For example, most
molecular, cytogenetic and histopathology laboratories provided their data separately and
are consequently reported separately even though they may be located in the same NHS
trust or hospital site. In contrast, some laboratories provide a service in collaboration with
other trusts, forming a single testing provider and are reported as such.
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Cumulative data
Cancer type
Breast
Lung
Bowel
Cancers of
blood, bone
marrow and
lymph nodes
Other
childhood
cancers
Muscle, bone
and soft tissue
Other
(including
brain,
melanoma of
the eye)
Total
Example of tests performed
HER2 ISH to determine
eligibility for targeted antiHER2 drug therapy
EGFR mutation testing to
determine eligibility for
targeted drug therapy e.g.
EGFR inhibitors
Mutation testing to determine
eligibility for targeted drug
therapy e.g. KRAS mutation
and KIT inhibitors
Mutation testing to inform
diagnosis and assess disease
activity and prognosis
Mutation detection to aid
diagnosis and guide
chemotherapy
Mutation testing to aid
pathologists in making the
diagnosis
Mutation detection to guide
chemotherapy
Number of tests
performed in
England
2010-2011
Estimated
cost
(£ million)
Reliability of
data
7.5k
£1.1
Medium (+/20%)
7.3k
£1.1
High (≥90%)
4.8k
KRAS: 4380
KIT: 465
£0.7
High (+/-5%)
74.2k*
£12.3
Medium to
high
1.0k
£0.2
Medium to
high
1.0k
£0.3
unknown
1.4k
£0.4
unknown
97.1k
£16.1
*This includes a small number of panel tests, which were counted as one test per panel, rather than
per gene
Completeness of data – number of tests
EGFR, KRAS, KIT: Data from all listed providers of these tests were included and the
number of tests is considered highly reliable. The number of EGFR tests closely matched an
industry estimate of 8,000 tests in 2011.
HER2: CPA laboratory listings were investigated but no single confirmed listing of HER2 ISH
test providers was made available due to confidentiality, and consequently some laboratories
may have been omitted from survey. Some of the laboratories included may provide testing
for the UK rather than just for England and this may have resulted in overestimation of tests.
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Cancers of blood, bone marrow and lymph nodes: All large testing centres provided data
for the survey but as testing is conducted by a variety of laboratories with a large range of
testing activity, the survey may underestimate the number of tests provided.
Other childhood cancers: Some laboratories record their activity by technology and had
difficulty separating activity by the categories requested. Therefore, the number of these
tests may be underestimated.
Completeness of data – estimated cost
The accuracy of the cost of testing cannot be fully guaranteed due to a variety of reasons
and therefore should be considered an estimate:
 Laboratories often have not costed their tests or have not done this recently. Where a
laboratory was unable to provide costs, the average cost of surrounding laboratories with
similar activity levels for the tests was used.
 Some laboratories’ prices cover the cost for pathologist input, some do not.
 Some laboratories charge a higher price externally than the cost of testing. Where this
discrepancy was reported (very small minority), the internal cost was used.
 FISH workload is often charged on a workload unit basis (rather than cost per test) and
therefore costs can vary widely between individual patients dependent on how complex
the analysis required is. The average figures were used.
The survey requested data on only NHS funded activity. In small number of cases, the
laboratories indicated they have submitted data for a mixture of NHS and privately funded
tests for KRAS and EGFR and because it was not possible to separate them accurately, they
are included. The number of these privately funded tests during the survey period is small,
particularly for EGFR, and the uncertainty is reflected in the “reliability of data” column.
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41
Annex E
Calculation of potential testing need for vemurafenib and crizotinib
The NICE Health Technology Appraisal of vemurafenib32 for the treatment of unresectable or
locally advanced BRAF V600 mutation-positive malignant melanoma commenced in
September 2011 and the outcome is awaited. A draft scope document for the proposed
health technology appraisal of crizotinib for the treatment of ALK fusion gene positive nonsmall-cell lung cancer has also been issued (June 2011)33.
Clinical response to vemurafenib and crizotinib is associated with particular patient subgroups with molecular markers that require identification using molecular testing approaches
and if adopted are likely to lead to an increase in the demand for molecular testing services.
Vemurafenib: calculation of projected demand for testing



The incidence of malignant melanoma skin cancer is currently increasing in England,
and in the most recently available data from 2008 malignant melanoma was found to be
the fastest increasing cancer in males and the second fastest in females . There were
9,695 new diagnoses of malignant melanoma in England in 200834. It is estimated that
approximately 10% of cutaneous melanomas have spread to distant body sites at the
time of initial diagnosis.
Vemurafenib is being considered for adults with locally advanced or metastatic malignant
melanoma positive for the BRAF V600 mutation.
If all patients presenting with metastatic melanoma were tested, the demand would be
approximately 1,000 tests. This approach does not take into account patients with locally
advanced melanoma, so test demand could be higher. In addition, some patients may be
too unwell for consideration of treatment, leading to a demand that would be lower than
the combined incidence of locally advanced and metastatic melanoma.
Crizotinib: calculation of projected demand for testing


32
33
34
The annual incidence of lung cancer in England is 32,54635. The two main categories of
lung cancer are non-small cell lung cancer (NSCLC; 80%, i.e. 26,036 patients) and small
cell lung cancers (nearly all of the remaining 20%, i.e.6,510).
Not all patients with a clinical or radiological diagnosis of lung cancer will be physically fit
enough to undergo a procedure to obtain cells or tissue for histological confirmation or
subsequent molecular testing. Figures from the most recent National Lung Cancer
Audit36 indicate that between 70-80% of lung cancer patients in England receive
histological or cytological confirmation of the diagnosis.
http://guidance.nice.org.uk/TA/Wave27/5
http://guidance.nice.org.uk/TA/Wave28/3
http://info.cancerresearchuk.org/cancerstats/types/skin/incidence/uk-skin-cancer-incidence-statistics
35
The CR-UK incidence figures (2008) have been used rather than more recent Lung Cancer Audit figures since the latter
are only obtained from hospital data and activity
http://info.cancerresearchuk.org/cancerstats/types/lung/incidence/
36
http://www.ic.nhs.uk/webfiles/Services/NCASP/audits%20and%20reports/NHS_IC_Lung_Cancer_AUDIT_2011_Interactive
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32, 546 lung cancer
patients per annum
6,709 patients (approx
20%) diagnosed with small
cell lung cancers
26,836 patients (80%)with
non small cell lung caner
7,811 (approx 30%)
patients present with
locally/regionally
advanced disease
7,811 (approx 30%)
present with locally
advanced disease
10,414 (approx 40%)
patients with advanced
metastatic disease
Tested for ALK status for prescription
of crizotinib
3,905 (approx 50%) of
these patients will have
surgery




Approximately 30% of patients with NSCLC present with localised, potentially operable
disease and in about 50% of these patients, surgery will be clinically appropriate. About
30% of patients present with locally/ regionally advanced disease (Stage IIIb) and 40%
with advanced metastatic disease (Stage IV, in which the cancer has spread to other
parts of the body).
Crizotinib is being considered for people with locally advanced or metastatic non-small
cell lung cancer whose tumours test positive for ALK gene rearrangements.
If all patients presenting with locally advanced or metastatic lung cancer were tested, the
demand would be approximately 18,000 tests. As some patients may be so ill as to be
ineligible for targeted treatment following a diagnostic procedure, actual demand may be
lower than this.
Increasing knowledge about the clinical and microscopic features associated with (and
therefore used to predict) the presence of a particular gene mutation means that by the
time ALK gene testing is introduced, it may be restricted to certain subtypes of NSCLC
e.g., adenocarcinoma and this may also lead to a reduced demand for testing.
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Annex F
Estimation of unmet testing need in cancer somatic mutation testing in England 20102011: a summary of work carried out by the Stratified Medicine Programme team at
Cancer Research UK
The Department of Health asked Cancer Research UK to attempt to quantify any unmet
need for cancer molecular testing in England, in order to assess the costs and health impact
of meeting this. Cancer Research UK surveyed English NHS supplier labs to understand the
number of tests being performed annually, and then surveyed a group of leading clinicians to
the estimate number of patients who should be getting these tests. The results indicated an
unmet need of around 5,000 EGFR tests per year in lung cancer and 0-8,600 KRAS tests in
colorectal cancer, with the range due to uncertainty around when KRAS testing fits best into
the clinical pathway.
Because approvals, guidance and unmet need are evolving all the time, the following figures
refer to the estimation of unmet need for the financial year 2010-2011 in order to match the
date range for which the activity survey was conducted. Any change in the estimated unmet
need since the end of the survey period has been explained in the text of the main
document.
Summary table illustrating calculation of unmet need for EGFR, KRAS, HER 2, and KIT
testing
Tumour/ gene
Number of
tests
performed
each year
NSCLC / EGFR
7,300
Anticipated need for
testing (based on
approved indications
and taking into
account patient fitness
for therapy)
12,500 (+/- 20%)
Potential unmet need
3,525 – 12,800
0 – c.8,600
Less than 500
Uncertain – mix of
diagnostic and predictive
testing performed and
current imatinib guidelines
do not stipulate
requirement for testing
None
c.5,000
(+/- 10%)
Colorectal cancer /
KRAS
Gastrointestinal
stromal tumour /
KIT+PDGFRA
4,380
Breast cancer / HER2
7,500
(+/- 5%)
465
(+/- 5%)
8,000
(+/- 20%)
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Methodology
1.
Number of test performed each year
To provide the best possible estimation of the potential current unmet need for
cancer somatic mutation testing in England, a survey was sent out to all laboratories
indicated to be involved in the provision of molecular testing to the NHS, including
private and NHS laboratories. Initial estimates had suggested there were 20
laboratories but further investigation identified 73 potential testing providers,
particularly for HER2 testing in breast cancer (see Annex D for further details).
These were contacted through a survey; 49 laboratories responded, of which 37
were providing testing and therefore supplied data to the survey. We received data
from all laboratories at major cancer centres and laboratories listed as providers of
KRAS, EGFR and KIT (for GIST) testing except for two laboratories who were
unwilling to participate in the survey. Activity data for these two laboratories was
estimated by Cancer Research UK.
The amount of KRAS tests delivered was surveyed prior to the revised guidelines
from NICE in March 2012, restricting approval for cetuximab to the first-line indication
for use prior to surgery to remove isolated liver metastases. Previous NICE
guidelines had also approved use for second and third line therapy, meaning a larger
potential clinical demand. The graphs here match the clinical need and tests
delivered from the same period i.e. 2010-2011.
Due to the high number of responses, we are confident of the completeness of the
data for EGFR, KRAS and KIT testing and the degree of uncertainty is indicated
through confidence intervals. For EGFR testing, national data was also received
from AstraZeneca, who set up the EGFR testing network and monitor EGFR testing
to understand gefinitib prescription patterns –their estimate of 8,000 is within the (+/10%) confidence levels. There is less certainty in the data for haematological testing,
but this service is well established and no unmet need is currently predicted.
2.
Anticipated need for testing:
A.
The anticipated need for testing was derived from incidence figures and modified
according to expert opinion on approach to identifying subgroups for testing.
Incidence figures
Incidence figures for the different tumour types have been identified from a number
of data sources:
Breast cancer / HER2: anticipated need based on annual incidence of breast cancer
in England of 39,97237 and 20% estimated rate of equivocal immunohistochemistry38.
Gastrointestinal stromal tumour / KIT+PDGFRA: Annual incidence in England and
Wales is 791 with estimated incidence in England of 700. 39
37
http://info.cancerresearchuk.org/cancerstats/incidence/
Walker RA, Bartlett JM, Dowsett A et al. HER2 Testing in the UK – Further Update to Recommendations. J Clin Path
10.1136/jcp.2007.054866
38
39
Gastro-intestinal stromal tumours (unresectable/metastatic) - imatinib (review): final appraisal determination. November 2011.
Accessed online at: http://www.nice.org.uk/newsroom/pressreleases/?domedia=1&mid=1596F0A9-19B9-E0B5D477B6FFB326ECF7
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Non-small cell lung cancer / EGFR: annual England incidence of lung cancer of
32,546 of which 80% are non-small cell type40,
Colorectal cancer / KRAS: annual incidence of 32,644 of which 29,380 (90%) will be
adenocarcinoma41.
B.
Approach to identifying sub-groups for testing
We understand that demand for testing cannot be based on incidence figures alone,
since testing is best performed in the setting of a stage of disease where further
treatment may be indicated. Also testing may not be appropriate in patients with
certain co-morbidities that increase the risk of toxicity from novel therapeutic agents,
giving an unfavourable risk to benefit ratio from treatment. To try to refine the
estimation of unmet need for existing tests, a number of oncologists, pathologists
and key opinion leaders were consulted, including representatives from the NCRN
Clinical Studies Groups (CSGs). These experts were asked to comment on the
situation based on their own experience of testing practices in their locality as well as
their knowledge of the situation nationally (this is summarised in an internal CR-UK
document)
Responses were received from thirteen representatives of the above groups in total
and there was broad agreement in the figures (apart from colorectal cancer/KRAS as
discussed further below).
3.
Considerations for unmet need
A.
KRAS Testing
Two approaches were put forward for the timing of KRAS gene mutation testing and
its use to guide identification of patients who may benefit from targeted therapy (e.g.
cetuximab) in metastatic colorectal cancer.
1. All patients who are diagnosed with metastatic colorectal cancer at the time of
diagnosis of metastatic disease.
This would mean that the result would be available immediately when cetuximab
therapy might be considered in the future, and would be likely to fit well into the
existing diagnostic pathway, with the test request being facilitated by the pathologist.
2. A subset of patients with a pattern of advanced disease meeting the approval
criteria set out by NICE for the use of cetuximab therapy, i.e. those in whom
cetuximab therapy would be immediately indicated and appropriate.
This would decrease testing volumes, but may increase cost per test and treatment
decision delays as the pathology paraffin block may have to be retrieved from an
archive and tested at a later point in the patient pathway.
Calculation of the unmet need is complicated by the fact that we do not know the
clinical circumstances of the 4380 patients who we have found are having tests
performed currently in order to refine the 0-8,600 tests unmet need figure. The most
conservative estimate for future testing would be to limit it to the 3,525 patients who
met the NICE guidance42 i.e. already covered by existing testing, but as we have
40
http://info.cancerresearchuk.org/cancerstats/types/lung/incidence/
41
http://publications.cancerresearchuk.org/cancertype/bowel/statslargebowel_2007.html
42
This changed in March 2012 due to revised NICE guidance and this is outlined in main document
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discovered there are other oncologists who would support and are already
requesting more widespread testing.
The situation has also been complicated by the recent decision announced by Merck
Serono, the manufacturer of cetuximab, to fund KRAS gene mutation testing for
every NHS patient at the point of the initial diagnosis of colorectal cancer. This may
lead to the testing of tumours from patients with early-stage disease who will never
require systemic treatments such as cetuximab.
B.
EGFR testing
The range of figures quoted for EGFR testing reflects different testing strategies
recommended by oncologists consulted, such as testing patients with
adenocarcinoma only, or testing all advanced non-small cell lung cancer patients
who would be fit enough for and considered for treatment. Gefitinib was formally
approved for first-line use in advanced non-small cell lung cancer with EGFR gene
mutation by NICE in July 2010, following the publication of draft guidance in May
2010. We have not adjusted the unmet need figure for the month covered by the
survey period before guidance was available since we believe that clinical practice
would reflect the anticipation of this decision in advance. If this was not the case then
the unmet need figure could potentially over-estimate the need for testing by a
maximum of 1/12 (8%) but this is within the confidence levels expressed in the table.
C.
Other
We have also heard that oncologists are accessing licensed targeted cancer drugs
for their patients through the interim Cancer Drug Fund. Since the Cancer Drug Fund
is currently coordinated and administered on a regional basis by strategic health
authorities, it is likely that there are variations in local interpretation of the guidelines
and evidence base and therefore decision-making process and resulting access to
novel cancer drugs.
The need for KIT and PDGFRA gene testing in gastrointestinal stromal tumour
(GIST) is less clear at present, and this seems to be used mostly by histopathologists
to provide support for a diagnosis of GIST in a small number of atypical cases. The
experts we spoke to anticipate a need for greater numbers of predictive tests in
future as more treatment options become available for patients with advanced GIST.
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Annex G
Glossary of terms
Biomarker: Substances that doctors can measure in the body to help them tell how a
disease is developing or how a treatment is working.
Biopsy: A small tissue sample obtained from the body using a hollow needle and processed
in a histopathology department in order to make a diagnosis.
Cytogenetic testing: Cytogenetic testing is the examination of the number or shape of
chromosomes present in a patient's sample. It does not provide any information about
specific genes or proteins that may be associated with a genetic disease.
Cytology: The process of obtaining a small sample of cells from the body and assessing
them for abnormalities in order to make a diagnosis of cancer or to look for early signs of
cancer or pre-cancerous conditions (such as in the NHS Cervical Screening Programme).
DNA: The molecular ‘building blocks’ of genes contained within the nucleus of a cell. The
genetic code of DNA is made up of four different molecules (abbreviated to A, C, T and G)
and determined by their sequence.
DNA sequencing: Technologies to determine the order (sequence) of the component units
of DNA, usually for comparison to one or more reference sequences.
Formalin: A chemical in widespread use in histopathology departments to preserve (‘fix’)
tissue as closely as possible to its fresh appearance during microscopic assessment.
Gene: A unit of inheritance, made up of DNA and containing the molecular code for a
protein product within a cell.
Genetic: referring to gene or changes at a gene level.
Germline mutation: A disease-causing change in DNA sequence that may be inherited.
Histopathology: The branch of medicine concerned with diagnosing disease in human cells
and tissues.
Immunohistochemistry (IHC): A laboratory technique to assess for the presence of certain
proteins in a tissue section, in order to help make a diagnosis or assess the amount of
protein.
In Situ Hybridisation (ISH): Use of probes that bind to particular markers in DNA. The
probes are visualized under the microscope and may be either fluorescent (FISH) or
coloured (chromagen, CISH) or silver (SISH).
Molecular diagnostic testing: Techniques carried out in NHS, research or private
laboratories to identify particular biomarkers of cells that help make a diagnosis or predict
the likelihood of a response to treatment.
Mutations: A gene mutation is a permanent change in the DNA sequence that makes up a
gene. Gene mutations can be inherited from a parent, occur before birth during development
or can happen during a person’s lifetime. Mutations passed from parent to child are called
hereditary mutations. Mutations that happen during a person’s life can be caused by
environmental factors such as ultraviolet radiation from the sun or toxins. They can also
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occur if a mistake is made as DNA is copied during cell division. Some gene mutations may
influence the risk of developing certain disorders, including cancer.
RNA: A type of molecule produced from DNA and acting as an intermediate and regulatory
step between DNA and proteins.
Reverse transcriptase polymerase chain reaction (rt-PCR): Used in combination with
FISH, this detects the presence of abnormal gene products resulting from changes in
chromosome structure, for example in soft tissue tumours.
Pathology blocks: Diagnostic tissue samples that have been preserved inside a block of
paraffin wax, from which extremely thin tissue sections can be cut. These can then be
placed on glass slides and stained for examination under the microscope in histopathology
or sent unstained to a laboratory for extraction of DNA and RNA and subsequent molecular
testing.
Somatic mutation: A disease-causing change in DNA sequence acquired during a person’s
lifetime, usually occurring because of errors arising when cells undergo repeated division.
Targeted Treatments: These treatments only attack cells showing particular proteins or
biomarkers. These are often specific biomarkers involved in tumour growth and progression
so attacking these aims to block the growth and spread of cancer.
Translocation: An abnormal change in chromosome structure, usually occurring
during cell division, and leading to rearrangement of genes.
50