RB1 (non-retinoblastoma cancer risk) – risk management

Retinoblastoma is a rare intraocular tumour that occurs in children, usually before age five years, and can involve one eye (unilateral) or both eyes (bilateral). 

• Retinoblastoma is due to detectable heritable pathogenic variants in the RB1 gene in:
  • 10-15% of unilateral cases^rr
  • 90-95% of bilateral cases^rr
• When bilateral disease is diagnosed but testing in blood does not detect a pathogenic variant, disease is due to either a germline cryptic (undetectable) heritable pathogenic variant or somatic mosaicism; in both situations this may involve the germline
• Pathogenic variants show an autosomal dominant pattern of inheritance
• Where there is no family history of retinoblastoma, the majority of affected individuals have a de novo pathogenic variant
• In some cases, a pathogenic variant is inherited from an apparently unaffected parent due to mosaicism or a pathogenic variant that displays reduced penetrance.^r

Heritable RB1 pathogenic variants are associated with an increased risk of retinoblastoma (unilateral and bilateral) and a range of non-retinoblastoma cancers. 

• Surveillance for retinoblastoma is not covered by this protocol (see Skalet et al. 2018;^r Soliman et al. 2017^r). 
• This protocol provides guidance for the management of non-retinoblastoma cancer risk in both those who have had retinoblastoma and those who have not.

The risk management schedule for an individual should take into account their clinical situation, if they have had retinoblastoma, any associated treatment and the monitoring required for treatment or following treatment.

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

• A known or obligate carrier of either an RB1 pathogenic variant or a rearrangement of chromosome 13 that includes the RB1 locus.
• A presumed carrier of a (cryptic) germline RB1 pathogenic variant due to the following:
  • an individual with bilateral retinoblastoma where genetic testing did not identify a heritable pathogenic variant in the RB1 gene; or
  • an individual with unilateral retinoblastoma and a family history of retinoblastoma where genetic testing did not identify a heritable RB1 pathogenic variant.

Exclusion criteria

• Relatives of a known RB1 pathogenic variant carrier whose genetic status has not been clarified.
• Individual with apparently sporadic unilateral retinoblastoma with no family history of retinoblastoma where genetic testing did not identify a heritable pathogenic variant in the RB1 gene (low risk of germline RB1 pathogenic variant; see Probability of cryptic heritable RB1 pathogenic variant in an isolated case of unilateral retinoblastoma; see Risks for probands and relatives to develop retinoblastoma and second cancers).
• Individual who has not had retinoblastoma but has a close relative who had bilateral/unilateral retinoblastoma and genetic testing did not identify a heritable pathogenic variant in the RB1 gene (low risk of germline RB1 pathogenic variant; see Soliman et al. 2017;^r see Probability of cryptic heritable RB1 pathogenic variant in an isolated case of unilateral retinoblastoma; see Interpretation of results in an isolated case of bilateral retinoblastoma; see Risks for probands and relatives to develop retinoblastoma and second cancers).
• Individual with mosaic or presumed mosaic RB1 pathogenic variant – management should be individualised after discussion with experts in the area.
• Individual with a variant of uncertain significance.

The majority of current published data estimates the cumulative second primary cancer risk to age 40 years is 28-33%. It is assumed the cumulative risk continues to rise after age 40.^r

* Reduced penetrance alleles include: (a) pathogenic variants in exons 1 and 2; (b) pathogenic variants in exons 24 to 27; (c) in-frame splice and intronic pathogenic variants; (d) missense pathogenic variants; and (e) large deletions encompassing both the RB1 and MED4 genes
** RB1 alleles with a parent of origin effect include: c.607+1G>T, c.1981C>T, c.608-16_608del, c.1331A>G and c.2663+2T>C
*** Source: Australian Institute of Health and Welfare (AIHW) 2022 Cancer Data in Australia; Canberra: AIHW. <https://www.aihw.gov.au/reports/cancer/cancer-data-in-australia/contents/cancer-risk-data-visualisation>. (2019 data, unadjusted for competing mortality)
# There is insufficient data to determine the long-term sarcoma risk for patients who did not receive radiation therapy; for comparison of risks for radiation therapy alone versus radiation therapy + chemotherapy see Wong el al. 2014^r
## Meta-analysis of risk of midline brain tumour for individuals with bilateral retinoblastoma, with adjustment for overestimation bias
⁺ No data available that is specific to the Australian RB1 population; in Australia, the general population melanoma risk is increased compared to other geographic regions

The choice of risk management strategy should take into account RB1 genotype^r and penetrance pattern,^r current age, other health issues and age-related cancer risk. Risks and benefits of interventions should be discussed with an experienced medical professional.

The impact of lifestyle on cancer risk should be discussed e.g. exercise most days for at least 30 minutes at moderate or strenuous intensity, maintain a healthy weight, have a healthy diet, limit alcohol intake, do not smoke, and avoid excessive sun exposure

^{^^} Gadolinium contrast, used in some MRI protocols, accumulates in the dentate nucleus and globus pallidus. The likelihood of this occurring increases with repeated dosing. Although there is no clear evidence of harm associated with this finding, longer-term prospective studies are needed

Patients with a history of heritable retinoblastoma are at increased risk for non-retinoblastoma second primary tumours (SPT), most commonly bone sarcoma, leiomyosarcoma, other soft tissue sarcoma, malignant melanoma, lung cancer and midline brain tumours.^rrrr There is emerging data that there may also be an increased risk of other common solid cancers, including bladder and breast cancer. 

Reduced penetrance RB1 pathogenic variants are associated with an increased risk of SPT, including an increased risk for carriers who have not had retinoblastoma, although there is insufficient data to accurately quantify the risk for this subgroup.^r

The SPT risk for patients who are somatic mosaics is unknown and screening for SPT in these individuals should be individualised.

The overall risk of developing a SPT is approximately 36% by 40 years after diagnosis of retinoblastoma. The magnitude of the SPT risk is influenced by the retinoblastoma treatment protocol. Changing treatment regimens over time mean it is difficult to give accurate specific risks for newly diagnosed children; however, the following general observations can be made:

• Radiation therapy is becoming less common in the treatment of retinoblastoma.
• The risk of a SPT is lowest in the group treated with enucleation or focal treatment only, higher for the group treated with radiation therapy, and highest for the group treated with radiation therapy plus chemotherapy.
• Radiation therapy is the strongest risk factor for sarcoma in the periorbital region.
• Radiation therapy plus systemic chemotherapy are the strongest risk factors for a second malignancy outside the radiation field.
• Certain systemic chemotherapy agents are associated with an increased risk of haematological malignancy (mainly leukaemia), and this risk is predominantly (but not exclusively) in the first three years after treatment and related to cumulative exposure.
• The impact of intra-arterial and intra-vitreal chemotherapy which are now routinely used, on development of SPT is currently unknown.^r

Sarcoma

The risk of sarcoma is influenced by the retinoblastoma treatment received and is higher in those who received systemic chemotherapy with radiation therapy.^rrr External beam radiation therapy has the strongest effect in the field exposed and there is a radiation dose–response relationship for all sarcoma types. Chemotherapy is a stronger risk factor for tumours outside the radiation therapy field. The risks of sarcoma vary by tumour location as well as patient age and sex (see figure 3 in article).^r

More than 50% of bone and soft tissue sarcomas occur in the head and neck, most often the periorbital region (e.g. orbit, nasal cavity, paranasal sinus), and risk is strongly linked to the use radiation therapy;^rrr however, surveillance MRI of the periorbital region has not been systematically studied.

A study of annual whole-body MRI (WBMRI) in a small cohort of retinoblastoma survivors demonstrated WBMRI can detect sarcoma, but with only modest specificity (92.1%) and poor sensitivity (66.7%).^r The positive predictive value of WBMRI was low (0.4).  

Published papers often do not give detail about the lower limits of the age range at diagnosis and where WBMRI is used there is no consensus about the age to start.^r When recommended, some experts suggest starting at age 8 years, and others recommend starting at either age 8 years or when the child is able to tolerate WBMRI without anaesthesia, whichever comes later. In non-irradiated patients, sarcomas typically present after a minimum of a 10-year latent period from the diagnosis of retinoblastoma. The latent period is shorter in patients who received radiation therapy, mainly for head and neck sarcoma (see figure 3 in article).^r

Where available, offer recruitment to research projects to evaluate surveillance protocols using whole body MRI (e.g. SMOC+ and SMOC junior: see ANZSA Clinical Trials and Studies).

Midline brain tumour

Trilateral retinoblastoma refers to the co-occurrence of unilateral or bilateral retinoblastoma and a midline brain tumour. Midline brain tumours are uncommon, with a risk of less than 2-5% for germline RB1 pathogenic variant carriers.^rrMost (approximately 75%) involve the pineal gland. Roughly one-third of midline brain tumours are diagnosed at the time of retinoblastoma diagnosis, providing support for baseline screening.^r More than 80% of midline brain tumours are diagnosed within three years of retinoblastoma diagnosis, and over 90% within five years.^r

There has been no systematic study of central nervous system (CNS) surveillance for midline brain tumours.  A recent meta-analysis of 211 published RB1-associated midline brain tumours reported a median survival of 9.4 months (95% CI, 8–13), with a 5-year survival rate of 15.5%.^r The survival was lower for children who had CNS symptoms (median 7 months; 5-year 0%) compared to children without CNS symptoms (median 32 months; 5-year 48.7%). Smaller tumours were also associated with better prognosis than larger tumours (tumour diameter 20 mm 5-year survival 60.5% versus tumour diameter ≥20 mm 5-year survival 13.5%). However, these data are subject to publication bias.

Although evidence for a benefit of ongoing surveillance for midline brain tumours is limited, many retinoblastoma treatment centres in the USA recommend brain MRI (including pineal images) every six months until age five years. This is not common practice in Europe where it is felt the burden of screening is too high given the small absolute risk of midline brain tumours.^r

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