Enrolled Taiwanese breast cancers
In current study, we presented the updated results of 648 TMO assays from 621 breast cancer patients (27 assayed twice) from the VGH-TAYLOR study. The distributions of clinical scenarios were: Group 1A (surgery first, n=387), Group 1B (recurrence within 3 years, n=25), Group 2 (neoadjuvant therapy first, n=93), Group 3-1 (de novo stage IV, n=36), and Group 3-2 (recurrence beyond 3 years, n=36). In addition, there were 71 subjects from retrospective biobank cohort. Twenty-eight patients were assayed twice, including 19 in Group 2 (diagnostic/post-neoadjuvant pair) and 8 in Group 1B. Fig 1 displays the distributions of IHC results and molecular subtypes.
Mutational maps of BRCA1/2
Among 648 breast samples, there were 18 truncating and 2 missense mutations in BRCA1 and 48 truncating and 1 missense mutations in BRCA2, impacting 3% (n=18) and 5% (n=29) of study cohort respectively (collectively altered in 6%, or 40 patients, Fig 2). Recurrent (observed at least twice) pathogenic/likely pathogenic mutations included W321*, K830fs, R1203*, Q1577* (BRCA1) and R3052Q, Q2829*, R2520*, S2186fs, K1472fs, S1722fs (BRCA2), with co-occurrence of BRCA1/2 in 7 breast cancers (log2 odds ratio > 3, both p- and q-value < 0.001, Fig 3). Regarding IHC phenotypes, there were 7 hormone receptor (HR)+/HER2- (39%), 2 HR+/HER2+ (11%), 2 HR-/HER2+ (11%), and 7 HR-/HER2- (39%) BRCA1 mutant breast cancers while for BRCA2 mutated cases, 19 (66%) were HR+/HER2-, 4 (14%) were HR+/HER2+, 3 (10%) were HR-/HER2+, and 3 (10%) were HR-/HER2-. It deserves notice that one HR+/HER2- patient harbored dual BRCA1 mutations (W1836* and A1729V), one HR+/HER2+ patient harbored triple BRCA2 truncating mutations (Q126*, Q1124*, Q3295*), four HR+/HER2- subjects with multiple BRCA2 mutations (range: 2-8), one HR+/HER2+ with dual BRCA2 mutations (Q649* and Q2829*), and another one HR-/HER2- with triple BRCA2 frameshift mutations (S538fs, T598fs, S973fs).
Among the 7 cases who were mutated in both BRCA1/2, three retrospective cohort patients including one HR+/HER2- with BRCA1 (Q1577*) and BRCA2 (R2520* and R3052Q), one HR-/HER2+ with BRCA1 (Q1867*) and BRCA2 (Q649* and Q2829*), and one HR+/HER2- with BRCA1 (R1720Q) and BRCA2 (W2970*) were reported. One Group 1B HR+/HER2+ with BRCA1 (Q855*) and BRCA2 (Q126*, Q1124*, Q3295*), one Group 3-1 HR-/HER2- with BRCA1 (S1180fs) and BRCA2 (S538fs, T598fs, S973fs), one Group 3-2 HR+/HER2- with BRCA1 (W321*) and BRCA2 (Q66*, Q2100*, E2220fs, Q2491*, R2494*, Q2506*, Q2823*, W2990*), and another one Group 3-2 HR+/HER2- with BRCA1 (W1836*, A1729V) and BRCA2 (Q1138*, Q2024*, W2626*) were also identified. Supplementary Fig 1 shows the chord diagram.
HRR genes
HRR genes defined by Heeke et al. were altered in 122 (19%) breast cancer samples while TBB interrogated genes (excluding BRCA1/2) were mutated in 107 (17%, Fig 4). Collectively, 164 (25%) of the 648 Taiwanese breast cancer samples were impacted by at least one HRR gene (Table 1 shows clinical presentations). The number of mutant HRR genes per sample ranged from 1 to 16 (median: 1, SD: 2.3) while 29 cases harbored more than one HRR mutated genes. Beyond BRCA1/2, the most prevalent HRR mutations came from ARID1A (7%), PTEN (7%), and PALB2 (6%), with the remaining genes impacting fewer samples than either of BRCA1/2 genes (Supplementary Fig 2). Clinically, there were 30 (75%) HR+/HER2-, 4 HR+/HER2+ (10%), 3 (8%) HR-/HER2+ and 3 (8%) HR-/HER2- ARID1A mutant breast cancers while four HR+/HER2- (G869fs/G869S, P225fs/P533fs, Q575*/Q1364*, Q743fs/E1718fs/S2256*), one HR+/HER2+ (Q199*, Q775*, Q1366*), one HR-/HER2+ (Q581*, Q670*, Q844*) and one HR-/HER2- (Q1363*, W1686*) breast cancers showed more than one ARID1A mutation within the same patient. The IHC distributions (HR+/HER2-:HR+/HER2+:HR-/HER2+:HR-/HER2-) for PTEN and PALB2 were 27(68%):1(3%):2(5%):10(25%) and 28(72%):2(5%):3(8%):6(15%) while multiple mutations per subject were noted in 9 HR+/HER2-, one HR+/HER2+ and another HR-/HER2+ PTEN mutant breast cancers as well as 6 HR+/HER2- and one HR-/HER2- PALB2 mutant cases. Trend of mutual exclusivity was observed between BAP1 and PALB2 (log2 odds ratio < -3, p-value: 0.717, q-value: 0.722) as well as BAP1 and RAD51C (log2 odds ratio < -3, p-value: 0.928, q-value: 0.928) while most HRR genes showed some degree of co-occurrence (Fig 5 shows the chord diagram). Mutation map of HRR genes other than BRCA1/2 is detailed in Supplementary Fig 3.