There is limited data on the effectiveness of cancer screening specifically in germline TP53 pathogenic variant carriers. Data about the utility of breast cancer and bowel cancer screening are mostly extrapolated from cancer screening studies in other groups at increased risk of these cancers. Comprehensive cancer screening protocols including whole-body MRI have shown benefit for screening, but were not randomised and are therefore subject to bias.rA meta-analysis showed 7% new, localised cancers were detected and treated with curative intent.r Issues that require clarification include defining the most appropriate screening protocol, and long term outcomes including survival benefit and psychosocial impact of intensive screening.r Enrolment in clinical trials is therefore encouraged whenever possible.
Studies have shown 37% of breast cancers are triple positive and 55% are HER2 positive among female TP53 pathogenic variant carriers. Male breast cancer has not been observed.r
There is strong evidence that bilateral mastectomy significantly reduces breast cancer risk in high-risk women.
There is limited data about the utility of breast MRI screening specifically in TP53 pathogenic variant carriers. In women with an increased risk of breast cancer due to a germline BRCA1 or BRCA2 pathogenic variant, breast MRI has been shown to detect more tumours and at an earlier stage than mammogram alone.
Similarly, there is no published study evaluating potential detrimental effect of ionising radiation (mammography) used for screening purposes in TP53 pathogenic variant carriers. However, there is a concern about the cumulative risk of mammograms in very young women exposed to mammograms for a long period of time and mammograms may be more difficult to interpret in younger women with denser breasts.
Risk reducing medication
Tamoxifen and raloxifene have been shown to reduce the risk of breast cancer in high risk women, although there is no specific data for TP53 pathogenic variant carriers. The lifetime breast cancer risk is sufficient to offer risk reducing medication. See COSA - Medications to lower the risk of breast cancer: clinician guide
Breast radiation therapy is associated with development of multiple new primary cancers of breast and adjacent local tissues in TP53 pathogenic variant carriers. Therefore, radiation therapy should be avoided where possible and therapeutic mastectomy considered in preference, and mammography avoided for screening if breast MRI is available.
Regular colonoscopy screening has been shown to significantly reduce bowel cancer risk in families at moderate-high risk. TP53 pathogenic variant carriers have a higher lifetime risk of developing colorectal cancer. Their risk is estimated at 2.8 times the population risk,r which is the equivalent of approximately 24% lifetime risk. Colorectal cancer also occurs at younger age (median age 40 years, compared with 71 years for sporadic colorectal cancer).r A retrospective review of 66 individuals with LFS reported initial colonoscopy findings.r Abnormalities were detected in 15 of the 31 patients who underwent colonoscopy. Cancer detection rate for colonoscopy is likely to be less than 16% as they were not performed as part of a screening study, and 2 of the 5 patients with colorectal cancer were symptomatic at the time of the procedure (personal communication). International consensus guidelines suggest that colonoscopy screening should commence at 25 years of age, or younger depending on family history. However, in this retrospective review, 4 out of 5 cancers were detected in patients less than 25 years of age,r and another study of whole-body MRI screening detected colorectal cancer in a patient 21 years of age, suggesting that screening should be considered from 20 years.
There is limited evidence for upper endoscopy screening for gastric cancer in LFS patients. Gastric cancer was found to occur in 15.8% of Asian patients with TP53 pathogenic variant, compared with 1% of North American and 3.6% of Europeans patients with LFS. This 8.9 times increased relative risk of gastric cancer is in excess of the 4.5 times increased risk of sporadic gastric cancer observed in Asian populations.r Although there are no studies evaluating the use of upper endoscopy in LFS patients, there is evidence that it may reduce mortality in high risk populations such as those of South East Asian and South American background.
The risk of cancer varies significantly by age and gender.r
See Number and type of first cancer by age group at the time of diagnosis.r
A recent prospective non-randomised study of comprehensive screening program including regular biochemical and imaging surveillance (MRI of the whole-body, brain and breast, and abdominal ultrasound) in germline TP53 pathogenic variant carriers reported 11 year follow-up results.r Early tumour detection through surveillance was associated with improved survival; 5- year overall survival of 88.8% (95% CI, 78.7-100) in the surveillance group vs 59.6% (95% CI, 47.2-75.2) in the non-surveillance group (p=0.0132). Other studies have documented the outcomes of baseline whole-body MRI screening.r The cancer detection rate was 6.7 to 9%, with a false positive rate of 15-87%. The higher rate of false positive with initial screening MRI is known from previous studies. Preliminary reports suggest that MRI screening, although intensive, may be accompanied by reduction in anxiety.r
Other cancers including lung, pancreatic, renal, prostate, melanoma and haematological cancers have an increased risk compared with the general population, however, this risk is not quantified.
TP53 pathogenic variants are believed to cause radiation sensitivity, due to impaired recognition and repair of DNA damage and there are numerous reports of second primary malignancies developing in areas previously treated with radiation therapy. Minimising radiation therapy is recommended where possible, especially if other treatment modalities with comparable cure rates are available. Similarly tests using ionising radiation should be avoided if other effective modalities are available.
There is evidence that smoking increases the risk of lung cancers in TP53 pathogenic variant carriers by 3-fold.