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POLE or POLD1 (polymerase proofreading polyposis) – risk management

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Polymerase proofreading-associated polyposis (PPAP) is an autosomal dominant condition caused by germline pathogenic variants in the POLE or POLD1 genes.

This risk management guideline has been developed for individuals who have NOT been diagnosed with a relevant cancer/tumour. The care of affected individuals should be individualised based on their clinical situation, and the monitoring they need as part of their treatment and post-treatment follow up.

The risk management of an individual with a pathogenic variant in two or more genes that confer a predisposition to cancer should also be individualised.

  • Known or obligate POLE  or POLD1 pathogenic variant carrier
  • Those at 50% risk of inheriting a POLE or POLD1 pathogenic variant

Exclusion criteria

  • Individuals diagnosed with other polyposis syndromes
Cancer/tumour type* Risk for this group by age 75 General population by age 75 yrs**
Colorectal  Increased but not quantified 3.9%
Duodenal adenomas Increased but not quantified Unable to obtain
Gastric fundic gland polyps Increased but not quantified Unable to obtain
Endometrial  May be increased 1.7%

*Although POLE and POLD1 are considered together, lifetime risk of cancer may vary by gene.rr
**Source: Australian Institute of Health and Welfare (AIHW) 2020 Cancer Data in Australia; Canberra: AIHW. <https://www.aihw.gov.au/reports/cancer/cancer-data-in-australia/>. (2016 data)

The choice of risk management strategy should take into account current age, other health issues and residual cancer risk.

Cancer/tumour type Recommendations*
Colorectal Surgical

Consider prophylactic colectomy if polyp burden not manageable with polypectomy.
Surveillance Age Strategy and frequency

From 25 years of age
  • 3 yearly colonoscopy unless polyps found.
  • If polyps detected, colonoscopy frequency should be determined by treating gastroentorologist based on polyp number, size and pathology.
Risk-reducing medication

Unless contraindicated, aspirin should be actively considered to reduce the risk of colorectal cancer. A low dose (100–300mg per day) is recommended from commencement of colonoscopy screening.
Duodenum Surgical

Consider duodenectomy for Stage IV adenoma.r
Surveillance Age Strategy and frequency

From 25 years of age
  • Upper gastrointestinal endoscopy every 5 years, or as directed by polyp load and/or dependent on Spigelman criteria.
Risk-reducing medication

There is no evidence to support the utilisation of risk-reducing medication outside a clinical trial.

*The impact of lifestyle on cancer risk should be discussed e.g. exercise regularly, maintain a healthy weight, have a healthy diet, limit alcohol intake, do not smoke and avoid excessive sun exposure.
**Increased risk of other tumour types has been suggested (including cancer of the breast, stomach, ovary and brain) but more research is required due to ascertainment bias in these initial studies.rr Screening and advice should therefore be based on the family history of these tumours.

The effectiveness of cancer screening in individuals with POLE and POLD1 pathogenic variants are still unclear. Recommendations have been extrapolated from cancer screening studies in other related hereditary cancer syndromes such as Lynch syndrome, MAP and attenuated FAP.

Colorectal cancer

Surgical

Data suggests polyposis may be more severe in POLE pathogenic variant carriers.rr For individuals with significant polyps (3 before 30 or >10 lifetime), recommendations are based on MUTYH associated polyposis (MAP) and includes colectomy when polyp burden becomes unmanageable.r

Surveillance

There is limited data regarding the appropriate surveillance frequency for individuals with POLE and POLD1 pathogenic variants. The recommendation for 3 yearly surveillance is thought to represent the best balance between risks and benefits of colonoscopy in individuals who have not yet had polyps identified.

Risk-reducing medication

There have been no studies providing beneficial evidence for the use of aspirin in POLE and POLD1 pathogenic variant carriers. However, considerable evidence supports the effectiveness of aspirin as risk-reducing medication for CRC in high-risk Lynch syndrome patients (>50% reduction in CRC risk).r Revised guidelines from the Cancer Council Australia have also made a strong recommendation to consider universal aspirin chemoprevention except where contraindicated, especially for those with excess cardiovascular risk.r Therefore, these recommendations have been included for individuals with POLE and POLD1 pathogenic variants.

Endometrial cancer

Surgical

No evidence of benefit in this population at this time.r

Surveillance

There is no evidence to support a survival benefit from transvaginal ultrasound (TVU) and aspiration biopsy. Where possible, surveillance should be offered in the context of a clinical trial.

Duodenum

There are no studies to show the efficacy of gastrointestinal endoscopy in reducing the risk for duodenal cancer. Surveillance recommendations have been based on the risk management guidelines for MUTYH associated polyposis (MAP) and attenuated familial adenomatous polyposis (AFAP).r

First degree blood relatives (parents/brothers/sisters/children) are at up to 50% risk of having inherited the pathogenic variant. More distant relatives may also be at risk of inheriting the pathogenic variant. Genetic relatives should be referred to a clinical genetics service or familial cancer centre to discuss predictive genetic testing.

Informing family members about hereditary cancer

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Version 5

Date Summary of changes
18/12/2019 "Mutation" changed to "pathogenic variant" throughout document for consistency among eviQ cancer genetics protocols per agreement among the cancer genetics reference committees' chairs. Definition of "pathogenic variant" added as a pop-up. Version number increased to V.5.
18/12/2020 The following sections of the protocol were updated to align with the revised eviQ cancer genetics risk management template:
  • Lifetime risk of cancer:
    • Heading changed to "Lifetime risk of cancer/tumour"
    • Risk for general population updated to include AIHW 2016 data
  • Cancer risk management guidelines:
    • Heading changed to "Cancer/tumour risk management guidelines"
    • Sentence added above table "The choice of risk management strategy should take into account current age, other health issues and residual cancer risk." 
    • Surveillance: "Age to begin" changed to "Age"
    • Other table formatting changes
  • Support and information: template wording updated.

Version 4

Date Summary of changes
19/10/2016 Discussed at 10 March 2016, reference committee meeting and protocol finalised over email, with 2 yearly review.  
31/05/2017 Transferred to new eviQ website. Version changed to V.2.
24/04/2019

Protocol reviewed and presented at Nov 2018 cancer genetics RCM. Discussion continued over email with the following changes made:

  • Summary: Specific mutations removed from first sentence. Sentence added at bottom to align with template changes.
  • Target group: Specific mutations removed from both target group and exclusion criteria.
  • Lifetime risk of cancer table: Statistics updated, risk age for general population changed to 75 yrs to align with POLE/POLD1 risk age. Specific mutations again removed.
  • Cancer risk management guidelines: Recommendations updated. Sentence below table updated to align with template changes.
  • Evidence for risk management guidelines: Evidence updated, namely colorectal surveillance and risk-reducing medication, and duodenum.
  • Support and information: Minor wording updates.
  • References: updated.

Version changed to V.3. To be reviewed in 2 years.
28/08/2019 Protocol title changed from 'Risk management for a PPAP (POLE/POLD1) mutation carrier' to 'POLE or POLD1 (polymerase proofreading polyposis) – risk management' in accordance with Cancer Genetics Reference Committees' consensus. Version number increased to V.4.

The information contained in this document is based on the highest level of available evidence and consensus of the eviQ reference committee regarding their views of currently accepted approaches to care or treatment. Any clinician seeking to apply or consult this document is expected to use independent clinical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. Use is subject to eviQ’s disclaimer available at www.eviQ.org.au

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The currency of this information is guaranteed only up until the date of printing, for any updates please check:

https://www.eviq.org.au/p/1913

01 Mar 2021