BRCA Detection Rate in an Italian Cohort of Luminal Early-Onset and Triple-Negative Breast Cancer Patients without Family History: When Biology Overcomes Genealogy

Toss, Angela; Molinaro, Eleonora; Venturelli, Marta; Domati, Federica; Marcheselli, Luigi; Piana, Simonetta; Barbieri, Elena; Grandi, Giovanni; Piombino, Claudia; Marchi, Isabella; Tenedini, Elena; Tagliafico, Enrico; Tazzioli, Giovanni; Cortesi, Laura

doi:10.3390/cancers12051252

Cited by 19 publications

(16 citation statements)

References 35 publications

(41 reference statements)

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“…Consistent with our findings, in a previous study, the BRCA1 mutation carriers had a higher incidence in TNBC than BRCA2 mutation carriers [ 40 – 43 ]. Moreover, in a recent work, Toss et al, showed that in TNBC Italian patients, BRCA mutation prevalence was 22.6% (21.4% BRCA1 ) and that 64.2% are ≤ 30 years old, which is in line with our findings [ 44 ]. Furthermore, Mahfoudh et al, reported that the 5382insC mutation in BRCA1 was detected in 25% (2/8) of Tunisian patients with TNBC [ 45 ].…”

Section: Discussionsupporting

confidence: 93%

Novel and recurrent BRCA1/BRCA2 germline mutations in patients with breast/ovarian cancer: a series from the south of Tunisia

et al. 2021

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Background The incidence of breast cancer (BC) and/or ovarian cancer (OC) is increasing in Tunisia especially in young women and mostly those with family history. However, the spectrum of BRCA mutations remains little explored in Tunisian patients in particular in the southern region. Methods We sequenced the entire coding regions of BRCA1and BRCA2 genes using next generation sequencing (NGS) in 134 selected patients with BC and/or OC. Results Among the 134 patients, 19 (14.17%) carried pathogenic mutations (10 are BRCA1 mutation carriers and 9 are BRCA2 mutation carriers) that are mainly frameshift index (76.9%). Interestingly, 5 out of the 13 variants (38.46%) were found at least twice in unrelated patients, as the c.1310-1313 delAAGA in BRCA2 and the c.5030_5033 delCTAA that has been identified in 4/98 BC patients and in 3/15 OC patients from unrelated families with strong history of cancer. Besides recurrent mutations, 6 variant (4 in BRCA1 and 2 in BRCA2) were not reported previously. Furthermore, 3 unrelated patients carried the VUS c.9976A > T, (K3326*) in BRCA2 exon 27. BRCA carriers correlated significantly with tumor site (p = 0.029) and TNBC cases (p = 0.008). In the groups of patients aged between 31 and 40, and 41–50 years, BRCA1 mutations occurred more frequently in patients with OC than those with BC, and conversely BRCA2 carriers are mostly affected with BC (p = 0.001, and p = 0.044 respectively). Conclusions The overall frequency of the BRCA germline mutations was 14.17% in patients with high risk of breast/ovarian cancer. We identified recurrent mutations as the c.1310_1313 delAAGA in BRCA2 gene and the c.5030_5033 delCTAA in BRCA1 gene that were found in 4% and 20% of familial BC and OC respectively. Our data will contribute in the implementation of genetic counseling and testing for families with high-risk of BC and/or OC.

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Section: Discussionsupporting

confidence: 93%

Novel and recurrent BRCA1/BRCA2 germline mutations in patients with breast/ovarian cancer: a series from the south of Tunisia

et al. 2021

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“…When we analyzed the distribution of BC molecular subtypes among BRCA1/2 mutated women, we confirmed the known association between TNBC and BRCA1 PVs (58.8%) and between luminal B BC and BRCA2 PVs (55.6%). 16 , 43 The scarce number of luminal A and HER2+ tumors among both BRCA1 and BRCA2 PV carriers is in line with the existing literature data. 16 , 43 …”

Section: Discussionsupporting

confidence: 82%

Mutational Analysis of BRCA1 and BRCA2 Genes in Breast Cancer Patients from Eastern Sicily

Stella¹,

Vitale²,

Martorana³

et al. 2022

CMAR

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Purpose Germline mutations of BRCA1 and BRCA2 are associated with a defined lifetime risk of breast (BC), ovarian (OC) and other cancers. Testing BRCA genes is pivotal to assess individual risk, but also to pursue preventive approaches in healthy carriers and tailored treatments in tumor patients. The prevalence of BRCA1 and BRCA2 alterations varies broadly across different geographic regions and, despite data about BRCA pathogenic variants among Sicilian families exist, studies specifically addressing eastern Sicily population are lacking. The aim of our study was to investigate the incidence and distribution of BRCA pathogenic germline alterations in a cohort of BC patients from eastern Sicily and to evaluate their associations with specific BC features. Patients and Methods Mutational status was assessed in a cohort of 389 BC patients, using next generation sequencing. The presence of alterations was correlated with tumor grading and proliferation index. Results Overall, 35 patients (9%) harbored a BRCA pathogenic variant, 17 (49%) in BRCA1 and 18 (51%) in BRCA2. BRCA1 alterations were prevalent among triple negative BC patients, whereas BRCA2 mutations were more common in subjects with luminal B BC. Tumor grading and proliferation index were both significantly higher among subjects with BRCA1 variants compared to non-carriers. Conclusion Our findings provide an overview about BRCA mutational status among BC patients from eastern Sicily and confirm the role of NGS analysis to identify hereditary BC patients. Overall, these data are consistent with previous evidences supporting BRCA screening to properly prevent and treat cancer among mutation carriers.

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“…Individuals with a gBRCA1 mutation are more likely to develop triple-negative BC (TNBC) than hormone receptor-positive (HR+) disease, whereas patients with gBRCA2 mutations tend to develop HR+ BC. gBRCA mutations are found in up to 23% of patients with TNBC and in 5% of patients with HR+ disease [16][17][18][19][20][21].…”

Section: Dna Repair Parp Inhibition and Synthetic Lethalitymentioning

confidence: 99%

An Overview of PARP Inhibitors for the Treatment of Breast Cancer

2021

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Loss-of-function mutations in BRCA1 and BRCA2 are detected in at least 5% of unselected patients with breast cancer (BC). These BC susceptibility genes encode proteins critical for DNA homologous recombination repair (HRR). This review provides an update on oral poly(ADP-ribose) polymerase (PARP) inhibitors for the treatment of BC. Olaparib and talazoparib are PARP inhibitors approved as monotherapies for deleterious/suspected deleterious germline BRCA-mutated, HER2-negative BC. Olaparib is approved in the USA for metastatic BC and in Europe for locally advanced/metastatic BC. Talazoparib is approved for locally advanced/metastatic BC in the USA and Europe. In phase 3 trials, olaparib and talazoparib monotherapies demonstrated significant progression-free survival benefits compared with chemotherapy. Common toxicities were effectively managed by supportive treatment and dose interruptions/reductions. Veliparib combined with platinum-based chemotherapy has also shown promise for locally advanced/metastatic BC in a phase 3 trial. Differences in efficacy and safety across PARP inhibitors (olaparib, talazoparib, veliparib, niraparib, rucaparib) may relate to differences in potency of PARP trapping on DNA and cytotoxic specificity. PARP inhibitors are being investigated in early BC, in novel combinations, and in patients without germline BRCA mutations, including those with somatic BRCA mutations and other HRR gene mutations. Ongoing phase 2/3 studies include PARP inhibitors combined with immune checkpoint inhibitors for the treatment of triple-negative BC. Wider access to testing for BRCA and other mutations, and to genetic counseling, are required to identify patients who could benefit from PARP inhibitor therapy. The advent of PARP inhibitors has potential benefits for BC treatment beyond the locally advanced/metastatic setting.

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BRCA Detection Rate in an Italian Cohort of Luminal Early-Onset and Triple-Negative Breast Cancer Patients without Family History: When Biology Overcomes Genealogy

Cited by 19 publications

References 35 publications

Novel and recurrent BRCA1/BRCA2 germline mutations in patients with breast/ovarian cancer: a series from the south of Tunisia

Novel and recurrent BRCA1/BRCA2 germline mutations in patients with breast/ovarian cancer: a series from the south of Tunisia

Mutational Analysis of BRCA1 and BRCA2 Genes in Breast Cancer Patients from Eastern Sicily

An Overview of PARP Inhibitors for the Treatment of Breast Cancer

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