According to the recommendations of all International Oncology Associations, BRCA genetic testing criteria are based on clinical-pathological characteristics of personal tumor and cancer family history. Pre-test counseling is performed beginning from a thorough examination of family history. It is common thought that hereditary cancers should develop in the context of a family seriously affected by the same disease. Nevertheless, several factors may limit the informativeness of the pedigree, such as inaccurate or incomplete information on family members, while our patient’s cancer could be the first in the family. Indeed, a prospective study of 306 women diagnosed with breast cancer at < 50 years of age, with no first- or second-degree relatives with breast or ovarian cancer, showed that those individuals with limited family history may have an underestimated probability of BRCA mutation, based on models relying exclusively on family history.25
Previous research helped define the clinical-pathological characteristics of BRCA-related tumors. In detail, BRCA1-associated tumors are poorly differentiated infiltrating carcinomas, more frequently ER and PR-negative and p53-positive.26,27 On the other hand, BRCA2-associated BC tends to be of higher grade than sporadic age-matched controls.28 Overall, BRCA-associated BCs are diagnosed at a young age and show a low frequency of HER2 expression.27,29 On these grounds, International Guidelines included the presence of young age at diagnosis and TN profile, regardless of family history, in the BRCA genetic testing criteria. Nonetheless, the cost-effectiveness of testing individuals with no tumor family history is still debated, especially in those countries where BRCA testing is offered by the National Health Service. Our study aimed to evaluate the rate of BRCA mutations in patients selected according to the biology and age of diagnosis of their tumors, in the absence of cancer family history.
Our analyses highlighted a mutation rate greater than 10% in the overall population of TNBC diagnosed ≤ 60 years (22.6%). In detail, BRCA testing was deemed cost-effective according to the NICE Guidelines up to 50 years, while in the subgroup of patients diagnosed between 51 and 60 years, detection rate was 7.9%, still cost-effective according to the last NCCN Guidelines. These results show differences from the previous literature. According to the literature, 15–30% of unselected TNBCs had confirmed BRCA mutations.30−32 Conversely, mutation prevalence decreased to 6–15% in patients without breast/ovarian cancer family history.31,33 This discrepancy could be explained by the fact that 37.1% of our patients were diagnosed ≤ 40 and 76.1% ≤ 50.Young age at diagnosis could therefore have increased the rate of BRCA detection compared to previous publications. According to the literature, the BRCA1 patients in our study were diagnosed at a younger age than non-carriers. On the other hand, the high rate of young TNBC patients in our population could be explained by the fact that TNBC is more common in young patients. Until 2016, moreover, we only tested patients diagnosed ≤ 40 years.
Interestingly, despite the cut-off for hormone-receptor negativity defined by the ASCO-CAP Guidelines,34 40% of the patients with ER between 1 and 9% (ER low positive) were observed to be BRCA1-positive at genetic testing. Previous analyses have already highlighted that tumors with ER < 10% clinically behave as ER < 1% tumors.35 Along with the results presented in this paper, these data indicate that for clinical purposes, tumors with ER < 10% and HER2/neu 0 or 1 + should be considered as TNBC. Furthermore, as reported in other analyses,27 3 out of 34 (8.8%) BRCA1-related tumors presented a more rare non-ductal histotype (in our study one medullary, one papillary and one lobular). Finally, no differences were observed between carriers and non-carriers in proliferation rate and the presence of bilateral tumors or second primary BC. Since 2013, patients at our Family Cancer Clinic have been offered rapid genetic counseling and testing at BC diagnosis. This strategy was demonstrated to improve the rate of risk-reducing bilateral mastectomy at the time of BC surgery,20 enabling us to reduce the risk of contralateral tumor in BRCA carriers.
In the second part of our analysis, we evaluated 109 patients diagnosed with luminal-like BC at ≤ 35 years. To our knowledge, this is the first study to evaluate the rate of BRCA mutation in luminal-like EOBC patients with no family history. This analysis is even more valuable in light of the EMBRACA trial results, in which talazoparib provided a significant PFS improvement over standard chemotherapy in patients with BRCA-related luminal-like advanced breast cancer.36 Overall and in each age subgroup (≤ 25, 26–30 and 31–35), BRCA detection rate was less than 10% (6.4%, 0%, 9% and 6%, respectively). Interestingly, all the patients diagnosed with EOBC under 26 years were observed to be negative at genetic testing, possibly underlining the need to evaluate other predisposing factors. No difference in proliferation rate was observed between carriers and non-carriers, contrary to what is reported in the literature.28 On the other hand, we found that BRCA2-positive luminal-like EOBCs were more likely associated to low PR expression, even if this type of evidence was only marginally significant due to the small sample available. Finally, as expected, most of hereditary luminal-like EOBCs were BRCA2-associated and HER2/neu negative, and all of them were to be accounted for as ductal carcinoma.
In conclusion, according to the last NCCN Guidelines, these results confirm the recommendation to test for BRCA genes TNBC ≤ 60 years, regardless of tumor histotype and by using immunohistochemical staining of less than 10% of nuclei for both ER and/PR as a cut-off. In luminal-like EOBC patients with no family history, on the other hand, a lower BRCA detection rate was observed yet overall > 5%, suggesting a role for other predisposing genes in this subset of patients.
Table 1
Characteristics of triple-negative breast cancer patients.
TNBC | Negative | BRCA1 | BRCA2 | p-value |
Number of patients (159) | 123 | 34 | 2 | * | ** |
Mean age at diagnosis (y) | 44,78 (24–59) SD 9,07 | 36,97 (26–54) SD 8,74 | 45,00 (39–51) SD 8,48 | 0.004 | < 0.001 |
Age group (y) <= 30 31–40 41–50 51–60 | 5 (4,0%) 31 (25,2%) 52 (42,3%) 35 (28,5%) | 9 (26,5%) 13 (38,3%) 10 (29,4%) 2 (5,9%) | 0 1 (50%) 0 1 (50%) | < 0.001 | < 0.001 |
Ki 67 (%) <=20 > 20 unknown | 11 (10,1%) 98 (89,9%) 14 | 1 (3,3%) 29 (96,7%) 4 | 0 1 (100%) 1 | 0.508 | 0.462 |
Bilaterality Yes No unknown | 5 (4,2%) 114 (95,7%) 4 | 4 (12,9%) 27 (87,1%) 3 | 0 2 (100%) 0 | 0.193 | 0.088 |
Histotype ductal lobular others unknown | 103 (95,4%) 0 5 (4,6%) 15 | 28 (90,3%) 1 (3,2%) 2 (6,5%) 3 | 2 (100%) 0 0 0 | 0.466 | 0.301 |
RO negative 1–9% unknown | 116 (95,1%) 6 (4,9%) 1 | 30 (88,2%) 4 (11,8%) 0 | 2 (100%) 0 0 | 0.321 | 0.226 |
* Comparison Negative vs BRCA1 vs BRCA2
** Comparison Negative vs BRCA1
Table 2
Characteristics of luminal-like early onset breast cancer patients.
EOBC | Negative | BRCA1 | BRCA2 | p-value |
Number of patients (109) | 102 | 2 | 5 | * | ** |
Mean age at diagnosis (y) | 31.95 (23–35) SD 2.85 | 34.0 (33–35) SD 2.93 | 30.6 (27–33) SD 2.89 | 0.488 | 0.353 |
Age group (y) <= 25 26–30 31–35 | 5 (4.9%) 20 (19.6%) 77 (75.5%) | 0 0 2 (100%) | 0 2 (40%) 3 (60%) | 0.688 | 1.00 |
Ki 67 (%) <=20 > 20 unknown | 35 (44.9%) 43 (55.1%) 24 | 0 1 (100%) 1 | 2 (50%) 2 (50%) 1 | 0.920 | 0.712 |
Bilaterality Yes No unknown | 5 (5.3%) 90 (94.7%) 7 | 1 (50%) 1 (50%) 0 | 0 5 (100%) 0 | 0.249 | 0.117 |
Histotype ductal lobular others unknown | 74 (91.3%) 3 (3.7%) 4 (4.9%) 21 | 2 (100%) 0 0 0 | 4 (100%) 0 0 1 | 1.00 | 1.00 |
PR <=20 > 20 unknown | 29 (33.7%) 57 (66.3%) 23 | 0 0 2 | 2 (40%) 3 (60%) 0 | 0.105 | 0.049 |
HER2 negative positive unknown | 54 (69.2%) 24 (30.8%) 24 | 0 0 2 | 5 (100%) 0 0 | 0.052 | 0.112 |
* Comparison Negative vs BRCA1 vs BRCA2
** Comparison Negative vs BRCA1