ENHANCED SURVEILLANCE OF HUMAN PAPILLOMAVIRUS (HPV) GENOTYPES IN CERVICAL DISEASE (ODR1516_354)

Department of Health and Social Care (DHSC) requires access to NHS England data for the purpose of the following research project:

Enhanced surveillance of human papillomavirus (HPV) genotypes in cervical disease (ODR1516_354)

The following is a summary of the aims of the research project provided by DHSC:

· To establish systems for prospective enhanced surveillance of HPV type-specific infections and HPV vaccination history for cervical disease.

Objectives of pilot:

· To identify (retrospectively) up to 125 cancers in women under 30 years in 2011.

· To pilot systems for the collection of enhanced surveillance data (vaccination status and type-specific HPV infection status), including systems for type-specific HPV testing of biopsy material.

UKHSA is establishing enhanced surveillance of cervical disease, starting with cancer cases in women <30 years in 2011/2012, to improve the information available about these ‘young’ cancers and to monitor the impact of the HPV immunisation programme on cervical disease endpoints in due course.

Vaccine uptake in catch-up cohorts was relatively low, and furthermore in the catch-up cohorts the vaccine was given to women with high rates of existing infection, therefore cancers in these birth cohorts, and especially those diagnosed in under 30 year olds, will continue to occur. This surveillance, monitoring the likely causative HPV type and immunisation status, will be important to maintain public trust in cervical cancer prevention programmes. It should also demonstrate the first impact of immunisation on disease end-points. Eligible cases will be identified either via cancer registries or via the network of Hospital Based Programme Coordinators (HBPC) and the relevant histopathology departments asked to submit a sample of archived lesion tissue to PHE for HPV typing. Data requested for each sample will include personal identifiable information to enable linkage to cancer registration data and to HPV vaccination records (if vaccination information unknown). A pilot in 2012 will aim to retrospectively recruit 125 cases diagnosed in 2011 (~40% of eligible cases). From 2012 onwards, we aim to prospectively identify cases via Cancer Registries. HPV type distribution in the sampled cancers will be described, overall and by vaccination status. Vaccine effectiveness against cancers in <30 year olds will be estimated by age at immunisation.

Background:

HPV immunisation (against HPV types 16 and 18) is now routinely offered to all 12-13 year old girls in the UK. The programme started in September 2008 and, during the first two years, included a catch-up programme targeting girls up to the age of 18 years (five catch-up cohorts). In England, the programme has achieved over 80% coverage for each routine cohort. Coverage between 38.9%-68.6% was achieved for the catch-up cohorts (Human Papillomavirus (HPV) vaccine uptake annual survey 2009/2010). The HPV vaccine used from 2008 to 2011 provides direct, prophylactic protection against HPV types 16 and 18 (Cervarix, GlaxoSmithKline). From September 2012, 12-13 year old girls have been offered the quadrivalent vaccine (Gardasil, Sanofi Pasteur MSD) which contains against types 16 and 18 and also types 6 and 11 (associated with the majority of genital warts).

The peak of cervical cancer incidence occurs in women in their 30’s: in 2008, 322 cases were diagnosed in women aged 35-39 years and 301 in women aged 30-34 years in England (ONS, 2008). A small number of cases are diagnosed each year in women aged under 30 years: 274 cases in 25-29 year olds and 40 cases in under 24 year olds in England in 2008 (Table 1) (ONS, 2008). Our baseline survey of HPV type distribution in women undergoing cervical screening and with cervical disease (in collaboration with Manchester) found that, in England, overall HPV 16/18 are associated with 76% of cervical squamous cell carcinomas (SCC), 82% of cervical adeno-squamous carcinomas 63.2% of cervical intraepithelial neoplasia (CIN) 3 and 90.7% of cervical glandular intraepithelial neoplasia (CGIN) (Howell-Jones et al, 2010). There was some evidence that a greater proportion of cervical cancers diagnosed in younger women are attributed to HPV 16/18, than those in older women i.e. HPV 16/18 were identified in 90% of SCC in 25-29 year olds in England (Howell-Jones et al, 2010).

In the long-run, the type-specific HPV infection status of cervical cancers amongst women targeted for HPV immunisation, and individual vaccination status, will be needed in order to evaluate the effectiveness of HPV 16/18 vaccination against cancer. Efficacy against cancer has not been directly measured in clinical trials that have used CIN/CGIN as surrogate endpoints. Current reporting of cancer cases to cancer registries does not include vaccination status or HPV infection status, and HPV status is not part of clinical testing for case management.

From 2012/13 onwards, questions may start to arise about cervical cancer cases occurring in young women of the age offered HPV vaccination (aged up to 22 years by 2012). The NHS Cervical Screening Programme in England invites women for cervical screening from 25 years of age (currently in Scotland and Wales, women are invited to screening from age 20 years, as they were in England up to October 2003). Although a reduction in cervical disease should be seen in the older catch-up birth cohorts, low vaccine coverage and pre-existing infection at time of vaccination will mean cancers may continue to occur, especially under 30 years of age, at rates that if unexplained could undermine public trust in the immunisation programme.

Knowledge of the HPV types present in cervical cancers occurring in young women and of their vaccination status should enable the effectiveness of HPV 16/18 vaccination to be monitored, the occurrence of cancer in ‘vaccinated’ birth cohorts to be explained and any deviations from expected impact to be identified and investigated as necessary. Once an efficient system is in place for enhanced surveillance of HPV-related cancers in young women, PHE will look to roll-out this enhanced surveillance to include other cases of cervical disease in due course.

This project builds upon collaborations with the NHS Cervical Screening Programme and colleagues in histopathology and virology at Manchester and some methods used in a study of HPV in archived cancers, CIN3/CGIN lesions and women undergoing cervical screening (Howell-Jones et al, Br J Ca 2010).

The following NHS England Data will be accessed:

· NDRS Cancer Registry data

The level of the Data will be:

· Identifiable

DHSC is the controller and processor as the organisation responsible for ensuring that the Data will only be processed for the purpose described above.

The lawful basis for processing personal data under the UK GDPR is:

Article 6(1)(e) - processing is necessary for the performance of a task carried out in the public interest or in the exercise of official authority vested in the controller;

The lawful basis for processing special category data under the UK GDPR is:

Article 9(2)(j) - processing is necessary for archiving purposes in the public interest, scientific or historical research purposes or statistical purposes in accordance with Article 89(1) based on Union or Member State law which shall be proportionate to the aim pursued, respect the essence of the right to data protection and provide for suitable and specific measures to safeguard the fundamental rights and the interests of the data subject.

Methods:

In 2012, UKHSA will investigate HPV-type distribution in 125 incident cervical cancer cases. Cases amongst women targeted (and potentially immunised) with HPV vaccine (born September 1990 onwards) and women not targeted for vaccination will be included. The oldest women who were eligible for HPV immunisation will be 21 years old in 2012.

From 2013 onwards, UKHSA will roll-out to other ages and disease grades, as required to monitor the impact of vaccination.

Consent from the patients not will be required/requested for data or for sample collection.

Identification of cases:

Pilot, 2012: Women eligible for inclusion in the pilot enhanced surveillance activity will be all women under 30 years of age diagnosed with invasive cervical cancer (squamous cell carcinoma or adeno/adenosquamous carcinoma: ICD code C53). These cancer cases will be identified retrospectively from data already collected in study investigating the history of presentation of cervical cancer in young women (collected by Amanda Ramirez and Anita Lim).

2013 onwards: Eligible cases will be identified either via Cancer Registries using the Encore system or via a network of Hospital Based Programme Coordinators (HBPC). Data will be requested from the Office for Data Release (ODR) annually until 18/04/2021 (when the data exchange agreement will be reviewed).

Data collection:

The following data items will be requested from the Cancer Registries for each submitted case:

1) Personal Identifying Information

· Patient Surname, Initials

· NHS number

· Date of birth

· Postcode (at time of diagnosis)

· Ethnic origin

· GP details (specifically; Patient practice code and Medical practitioner)

2) Details of cancer diagnosis:

· Date of diagnosis

· Histology classification (e.g. squamous, adeno, adenosquamous, small cell carcinoma)

· Stage of tumour (FIGO)

· Hospital details (specifically Hospital name and consultant name). To include hospitals attended at date of diagnosis and in preceding and following 6-months to ensure identification of the diagnosing and treating hospital.

Details on diagnosing and treating hospitals will be used to identify the correct contact to request a cancer tissue section. Collection of personal identifying information (including patient surname and initials, NHS number, date of birth) will be used for patient identification when requesting tissue specimen and vaccination status. Collection of date of birth and ethnicity will be used to stratify HPV test results and potential vaccine failures by ethnicity and age. Collection of GP details will allow us to contact the GP to obtain vaccination status. Where GP details aren’t available, or where a GP does not hold the relevant records, patient postcode will be used to identify the relevant child health record department. Collection of the date of cancer diagnosis will also facilitate patient identification when requesting the tissue specimen. We will request that the relevant clinician confirms patient date of birth and date of diagnosis is consistent with their medical records. The collection of other cancer diagnosis details (including cancer classification, stage of tumour) will be used help inform the risk of vaccine failures in young women.

Data should be sent to PHE HPV surveillance team either in an encrypted email or by post (fully addressed to a named individual). Once data submitted in paper-format have been entered onto the appropriate database, the temporary document containing PII will be destroyed as confidential waste. All PII will be handled in compliance with the recommendations of the Caldicott Report and the relevant legislative framework.

Collection of cancer samples

The relevant laboratory or histopathologist will be identified from information provided by the registry/HBPC and informed of the enhanced surveillance and invited to participate. Once participation is confirmed, a relevant contact will be identified and details identifying the case (Full name, NHS number, date of birth, date of cancer diagnosis, cancer histology, stage of tumour and treatment received) will be sent either by encrypted email or by post in a double envelope (fully addressed to this named individual and marked “PRIVATE AND CONFIDENTIAL” on the inner envelope only) along with a letter providing details of the proposed enhanced surveillance.

Participating histopathology laboratories will be asked to send sections of wax-embedded blocks to a central laboratory (PHE Virus Reference Department (VRD)).

In the pilot year, UKHSA will aim to retrospectively collect up to 125 cancer cases diagnosed in 2011. This represents about 40% of the maximum number of cancers cases expected in under 30 year olds.

UKHSA do not propose to collect a blood sample for HPV antibody testing, but the holding of patient identifiers (see below) means this could be reconsidered if accurate vaccination histories prove difficult to collect, or suspicion of vaccine failures needed further investigation. However, for cases in the catch-up cohorts, cancer following well-documented vaccination is more likely to be due to prior infection than due to vaccine failure, and therefore investigation of serological responses will probably not be justified.

The proportion and representativeness of the included cases will be determined by comparison to cases reported to East Midlands Cancer Registry (the lead cancer registry for gynaecological cancers) in due course.

Sample processing and HPV testing and genotyping

Results of HPV testing will not be returned to the reporting clinician (or patient) as the in-house assay (described below) is not validated for diagnostic work and current treatment options for cervical disease do not depend upon the HPV genotype(s) detected. This may need to be reconsidered if the HPV status becomes clinically relevant and clinicians (or patients) request the results of our testing. The proposed methods for sample processing and HPV testing, to be evaluated in the pilot, are outlined below:

Sample preparation: Wax embedded material will be de-waxed to prepare a test specimen by adding a 1 ml of octane to each Eppendorf tube followed by 75 ml of methanol. Tubes will then be vortexed and incubated at 56C for 30 min followed by centrifugation at 13 000 r.p.m. for 1 min after which the octane layer can be removed using a fine-tipped Pasteur pipette. The tissue pellet will then be washed with 1.0 ml of ethanol, centrifuged as before and the ethanol removed. The tubes will then be left at 56C for 30–45 min to evaporate off residual ethanol.

DNA extraction: Total nucleic acid will be extracted using the BioRobot Universal System

HPV testing:

Extracted material will be subjected to HPV L1 DNA amplification using a single-round HPV Multiplex PCR incorporating modified HPV GP5+ and GP6+ oligonucleotides and a human pyruvate dehydrogenase ‘housekeeping’ gene-based PCR to control for specimen integrity. Biotinylated PCR products will be hybridized against amino-tagged oligonucleotide probes representing HPV types 6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68 coupled to spectrally distinct 5.5 μm diameter polystyrene beads. PCR-probe-specific hybridizations will then be determined using a Luminex 200 analyzer.

Determination of HPV vaccination history:

We will contact the patient’s General Practitioner (or NHAIS Exeter system) to obtain full HPV vaccination data from their medical records (including vaccine given, date of immunisation and number of doses received). Patients will be identified using confidential patient information (NHS number, Surname, Initials, Date of Birth). If no record of HPV vaccination history is identified on these systems, we will use other locally held immunisation information systems (i.e. Child-Health Immunisation records). PII will only be sent to named individuals and will be transferred by post (in an envelope marked “CONFIDENTIAL”) or via encrypted email. Vaccination data requested will include the following:

Detailed HPV vaccination data for women in eligible cohorts

· Dates of immunisation

· Vaccine received

· Number of doses received

Data analysis:

Pilot: The HPV type-specific epidemiology of cervical cancers in women aged <30 years in England will be described by available variables (age, birth cohort, region, ethnicity (where data are available) and vaccination status).

Vaccine effectiveness, with 95% confidence intervals, against vaccine type (HPV 16/18) cervical cancer will be estimated using the following equation (Farrington, 1993):

Vaccine effectiveness = 1 – [PCV(1-PPV)]/[1-PCV)PPV],

where PCV is the proportion of cases vaccinated and PPV is the proportion of the population that is vaccinated.

In 2011/2012, it is expected that the vast majority of cases of cervical cancers under 30 will be in the older birth cohorts that have not been offered HPV vaccination, with probably less than 20 cases in women under 22 years (targeted for HPV immunisation). This offers the opportunity to develop and pilot the surveillance system before the resulting data are in high demand, and to gather some baseline (pre-immunisation) data on HPV type-distribution in these rare but important young cancer cases.

Ethics and Approvals:

The enhanced surveillance of HPV-associated severe cervical disease falls under PHE’s cover under section 251 of the National Health Services Act 206 and Statutory Instrument 2002 No. 1438, the Health Service (Control of Patient Information) Regulations 2002, to process personal identifiable information (PII) for surveillance purposes. The NIGB confirmed that the activity would fall under these regulations. Research Ethical Committee and Research Governance approval are therefore not required.

Data security:

Data will be held and shared in compliance with PHE policies on data security. A System Level Security Policy has been established for this enhanced surveillance system and the system will be subject to information risk assessment, including security risks.

Reporting of results from the enhanced surveillance will be compliant PHE policies on the publication of small cell sizes and reference to particular geographical areas that might allow deductive disclosure of individuals.

The Data will not leave England/Wales at any time.

All personnel accessing the Data have been appropriately trained in data protection and confidentiality.

There will be no requirement and no attempt to re-identify individuals when using the Data.

Using this data, UKHSA will conduct analyses of the rate of cervical cancer diagnoses in females under the age of 30 years, stratified by birth cohort, from 2000 to 2021 (i.e. the most recently available cancer registration data). Analyses will also be conducted comparing women ineligible for vaccination (i.e. born between 01/09/1985 and 31/08/1990), women eligible for older catch-up vaccination (i.e. vaccinated at 16-18 years of age), eligible for younger catch-up vaccination (i.e. vaccinated at 14-15 years of age), and eligible for routine vaccination (i.e. vaccinated at 12-13 years of age).

These data will be used to produce evidence and outputs that will inform the monitoring and evaluation of national HPV vaccination in females in England. This will inform policy to improve health outcomes in this population.

Data thus far have not yet evidenced impact of vaccination in this population; however, surveillance has been established to monitor any relevant changes and will need to be updated with more recent years' data.