Second primary cancers following breast cancer in the general population and in BRCA1 and BRCA2 pathogenic variant carriers

Background Second primary cancer (SPC) risks in breast cancer (BC) survivors carrying BRCA1 or BRCA2 pathogenic variants (PVs) are uncertain. There is also little evidence for how SPC risks following BC vary by sociodemographic factors, treatments, or the pathology of the first BC. My objectives were to estimate combined and site-specific SPC risks in Breast Cancer Gene 1 and 2 (BRCA1 and BRCA2) PV carriers, and to characterise the variability in SPC risks by sociodemographic factors, treatments, and first BC pathology in BC survivors largely untested for BRCA1 or BRCA2 PVs. Methods I first examined the existing literature on SPC risks following BC in males and females in two separate systematic reviews. In each review I searched for relevant studies published by March 2022 and pooled the reported standardized incidence ratios (SIRs) for overall SPCs and site-specific SPCs by age at first BC onset, time since BC onset, and geographic region using random-effects models with DerSimonian-Laird estimators. I then a used a novel linkage of population-scale electronic health records from the Hospital Episode Statistics Admitted Patient Care dataset, Hospital Episode Statistics Outpatients dataset, and National Cancer Registration Dataset from the National Disease Registration Service to identify a cohort of 581,403 females and 3562 males diagnosed with BC between 1995 and 2019 in England. Finally, for the first time, I linked the above data to germline genetic testing data from regional molecular genetics laboratories across England to identify a cohort of 25,811 females and 480 males diagnosed with BC and tested for a germline BRCA1 or BRCA2 PV between 1995 and 2019. In each cohort, I estimated SIRs using gender-, age-, calendar-year-, and site-specific incidences for England, estimated hazard ratios using Cox regression, and estimated cumulative risks with Kaplan-Meier analyses. Results The key findings from the systematic reviews were that both males and females are at elevated non-breast SPC risks compared to the corresponding population-level risks at combined and specific sites. Among all BC survivors diagnosed 1995-2019 in England, I observed particularly high SIRs for contralateral breast cancer (CBC), endometrial, and prostate SPCs and saw a clear elevation in SPC risks for BC survivors diagnosed when younger or in more deprived regions. Finally, I saw clearly increased risks of CBC, ovarian, and combined non-breast/ovarian SPCs in BC survivors carrying BRCA1 or BRCA2 PVs compared to BC survivors without a PV in either gene, and also saw significantly elevated colorectal SPC risks in female BRCA1 PV carriers, pancreatic SPC risks in female BRCA2 PV carriers, and CBC and prostate cancer risks in male BRCA2 PV carriers. Interpretation This work offers proof of principle that linkages of genetic testing laboratory data to population-scale electronic health records data allow estimation of understudied cancer risks in novel cohorts, and offers evidence in favour of enhanced CBC and ovarian cancer surveillance and risk-reducing options in BC survivors carrying BRCA1 and BRCA2 PVs. The clear differences by socioeconomic status in SPC risks following BC in the general population may also have policy implications, and the clearly elevated SPC risks in females diagnosed with first BC at under age 50 could inform future cost-benefit analyses considering surveillance recommendations for BC survivors.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2024

Author dc:creator

• Allen, Isaac

Advisor dc:contributor.advisor

• Antoniou, Antonis

• Epidemiology
• Breast cancer
• Second primary cancer
• Risk
• BRCA1/2
• Pathogenic variant

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/c52c4a88-7cee-4573-8a7a-b8d79fe7933a/download
• https://creativecommons.org/licenses/by/4.0/

Language dc:language

eng

Author Identifier

0000-0003-4640-3617

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/376465