The impact of germline genotype on breast cancer tumour phenotype and outcome

Abstract

Breast cancer susceptibility gene panels are increasingly utilised in mainstream oncology diagnostic practice. This work describes the influence of commonly reported high and moderate penetrance genes on tumour histopathological phenotype, somatic mutational profile and clinical outcome for symptomatic, early onset breast cancer patients. It considers how genetic testing can be utilised to identify actionable risk and interpret Variants of Uncertain Clinical Significance (VUS).
Participants from the Prospective Outcomes in Sporadic Versus Hereditary Breast Cancer (POSH) Study (n=2744) were included. Tumour histopathological characteristics including grade, size, focality, hormone receptor status, nodal involvement and lymphovascular invasion were compared between gene carriers (BRCA1+, BRCA2+, PALB2+, CHEK2+, ATM+ and TP53+) and non-carriers. Kaplan Meier analysis was used to estimate differences between carriers and no-carriers for Overall Survival (OS) and Distant Disease-Free Survival (DDFS). A further sample with tumour sequence data and a greater range of onset ages was included for comparison from The 100,000 Genomes Project (100KGP) (Rare Disease, Familial Breast Cancer (n=826) and Cancer, Breast Cancer (n=2464)). Tumour Mutational Burden (TMB) and the presence of Single Base Substitution (SBS) Mutational Signatures were compared between gene carriers and non-carriers.
In the POSH study, 16.7% (453/2744) had a moderate or high penetrance variant. Hormone receptor status and tumour focality were significant independent predictors of BRCA1+ and BRCA2+. BRCA1+ were significantly more likely to present with a Triple Negative Tumour (TNT) (123/201 (61.2%) versus 417/2291 (18.2%)) (p<0.0001) and be localised (156/180 (86.7%) versus 1461/2085 (70.1%)) (p<0.0001)). BRCA2+ were significantly more likely to be ER-positive (115/136 (84.6%) versus 1557/2279 (68.3%)) and multifocal at presentation (57/121 (47.1%) versus 624/2085 (29.9%) (p<0.0001)). Within 100KGP, BRCA+ and PALB2+ had a significantly higher TMB compared to non-carriers (BRCA+, 4.39 Mut/Mb and PALB2+, 6.39 Mut/Mb versus 2.51 Mut/Mb) (p=0.0433 and p=0.0066 respectively). BRCA+ and PALB2+ also had a significantly increased expression of SBS3 compared to non-carriers (31.14% and 32.14% versus 10.59%) (p<0.0001 and p=0.0047 respectively). CHEK2+ presented with breast cancer that was significantly more likely to be ER-positive compared to non-carriers (p=0.0016). Survival analysis revealed that OS and DDFS was significantly worse in CHEK2+ versus CHEK2- (OS HR, 1.58 (95%CI, 1.01-2.48 (p=0.043))).
Tumour phenotypic characteristics including focality, hormone receptor status, TMB and SBS mutational signature contribute to estimating the likelihood of a BRCA1, BRCA2 or PALB2 germline variant and could be used to assist with the interpretation of a VUS. The utility of tumour phenotype in moderate risk gene carriers for likelihood prediction and variant interpretation is less clear.

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ORCID for William Tapper: orcid.org/0000-0002-5896-1889

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