BRCA detection rate in an Italian cohort of luminal early-onset and triple-negative breast cancer patients without family history: when biology overcomes genealogy.

Abstract BACKGROUND: NCCN Guidelines recommend BRCA genetic testing in individuals with a probability >5% of being a carrier. This analysis aimed to evaluate the rate of BRCA mutations in triple-negative breast cancer (TNBC) patients diagnosed ≤60 years and luminal-like breast cancer (BC) patients diagnosed ≤35 without breast and/or ovarian family history. METHODS: 159 TNBC patients diagnosed ≤60 years and 109 luminal-like BC patients diagnosed ≤35 years without family history were retrospectively identified. Mutation prevalence and clinical-pathological characteristics associated with mutational status were evaluated. RESULTS: In TNBC patients, BRCA mutation prevalence was 22.6% (21.4% BRCA1 and 1.2% BRCA2). BRCA1-related TNBC patients were younger (p <0.001). Mutation prevalence was 64.2% ≤30 years, 31.8% in patients aged 31-40, 16.1% for those aged 41-50 and 7.9% for those between 51 and 60 years of age. A total of 40% of patients with estrogen receptor (ER) 1-9% were BRCA1 carriers. BRCA detection rate in early-onset BCs was 6.4% (1.8% BRCA1 and 4.6% BRCA2). Mutation prevalence was 0% 0-25 years, 9% 26-30 years and 6% 31-35 years. BRCA2-positive luminal-like early-onset BCs were more likely associated with low progesterone receptor (PR) expression (p = 0.049). CONCLUSIONS: BRCA genetic testing is recommended in TNBC diagnosed ≤ 60 years, regardless of cancer family history, histotype and by using immunohistochemical staining <10% of nuclei for both ER and/PR as a cut-off. In luminal-like early-onset BC patients, a lower BRCA detection rate was observed, suggesting a role for other predisposing genes.

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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

Cancers ◽

10.3390/cancers12051252 ◽

2020 ◽

Vol 12 (5) ◽

pp. 1252 ◽

Cited By ~ 1

Author(s):

Angela Toss ◽

Eleonora Molinaro ◽

Marta Venturelli ◽

Federica Domati ◽

Luigi Marcheselli ◽

...

Keyword(s):

Breast Cancer ◽

Genetic Testing ◽

Family History ◽

Triple Negative Breast Cancer ◽

Early Onset ◽

Detection Rate ◽

Triple Negative ◽

Brca2 Mutation ◽

Brca Testing ◽

Brca Genetic Testing

NCCN Guidelines recommend BRCA genetic testing in individuals with a probability >5% of being a carrier. Nonetheless, the cost-effectiveness of testing individuals with no tumor family history is still debated, especially when BRCA testing is offered by the national health service. Our analysis evaluated the rate of BRCA pathogenic or likely-pathogenic variants in 159 triple-negative breast cancer (TNBC) patients diagnosed ≤60 years, and 109 luminal-like breast cancer (BC) patients diagnosed ≤35 without breast and/or ovarian family histories. In TNBC patients, BRCA mutation prevalence was 22.6% (21.4% BRCA1). Mutation prevalence was 64.2% ≤30 years, 31.8% in patients aged 31–40, 16.1% for those aged 41–50 and 7.9% in 51–60 s. A total of 40% of patients with estrogen receptors (ER) 1–9% were BRCA1 carriers. BRCA detection rate in early-onset BCs was 6.4% (4.6% BRCA2). Mutation prevalence was 0% between 0–25 years, 9% between 26–30 years and 6% between 31–35 years. In conclusion, BRCA testing is recommended in TNBC patients diagnosed ≤60 years, regardless of family cancer history or histotype, and by using immunohistochemical staining <10% for both ER and/PR. In luminal-like early-onset BC, a lower BRCA detection rate was observed, suggesting a role for other predisposing genes along with BRCA genetic testing.

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Germline Mutations in Triple-Negative Breast Cancer

Breast Care ◽

10.1159/000455999 ◽

2017 ◽

Vol 12 (1) ◽

pp. 15-19 ◽

Cited By ~ 25

Author(s):

Eric Hahnen ◽

Jan Hauke ◽

Christoph Engel ◽

Guido Neidhardt ◽

Kerstin Rhiem ◽

...

Keyword(s):

Breast Cancer ◽

Family History ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Positive Family History ◽

Therapy Response ◽

Hereditary Disease ◽

Biological Entity ◽

Breast Cancer Predisposition ◽

Mutational Status

Triple-negative breast cancer (TNBC) is associated with a poor prognosis and defines a subgroup of patients who do not benefit from endocrine or anti-HER2 therapy. Rather than being a biological entity, TNBC represents a heterogeneous disease, and further subtyping is necessary to establish targeted therapies. Germline mutational status may serve as a robust biomarker predicting therapy response, especially with respect to compounds challenging the DNA repair machinery. Patients with TNBC usually show an early onset of the disease, as well as a positive family history of breast and/or ovarian cancer in more than one third of all cases, which suggests that TNBC is closely associated with a hereditary disease cause. In unselected TNBC cases, the prevalence of pathogenic germline BRCA1/2 mutations is approximately twice as high as in breast cancer overall. Early age at diagnosis and positive family history are strong predictors for an increased BRCA1/2 mutation probability, which is up to 40% when both risk factors are considered. Apart from BRCA1/2, the rarely mutated breast cancer predisposition genes PALB2 and FANCM have been associated with TNBC. This review summarizes the role of germline mutational status in TNBC pathogenesis. Clinical trials addressing BRCA1/2 mutation carriers are discussed.

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A Case of Triple-Negative Breast Cancer with Germline Pathogenic Variants in Both BRCA1 and BRCA2

Case Reports in Oncology ◽

10.1159/000520148 ◽

2021 ◽

pp. 1645-1651

Author(s):

Miyuki Kitahara ◽

Yasuo Hozumi ◽

Mitsuki Machinaga ◽

Yuka Hayashi

Keyword(s):

Breast Cancer ◽

Genetic Testing ◽

Family History ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Ductal Carcinoma ◽

Outer Part ◽

Left Breast ◽

Cancer Syndrome ◽

Pathogenic Variants

We report a rare case of hereditary breast and ovarian cancer syndrome (HBOC) with pathogenic variants in both BRCA1 and BRCA2. The patient was a 78-year-old woman who visited the hospital after noticing a lump in her left breast 6 months before, which gradually increased in size. According to her family history, her maternal aunt developed breast cancer in her 40s. On palpation, a 4-cm large mass was palpated in the upper outer part of the left breast. A needle biopsy revealed invasive ductal carcinoma of the breast, which was negative for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor type 2. The patient was diagnosed with cT2N0M0 stage IIA, and primary systemic treatment was planned. The patient developed drug-induced interstitial pneumonia after receiving paclitaxel. Although she recovered spontaneously, she did not wish to receive further chemotherapy, and thus surgery was performed. Four months after the surgery, the patient became aware of dyspnea. After a thorough examination, she was diagnosed with postoperative cancer recurrence of the left breast with multiple liver metastases, cancerous peritonitis, multiple bone metastases, and multiple lymph node metastases. Genetic testing was performed, and pathogenic variants were found in both BRAC1 and BRCA2. However, her condition worsened, and she died 8 months after the surgery. BRCA pathogenic variants had more advanced breast cancer on initial diagnosis and worse cancer-related outcomes. It is desirable to consider the optimal approach to the treatment of breast cancer in pathogenic variants. In elderly patients with triple-negative breast cancer, HBOC may be suspected, based on biomarkers and family history. It is important to provide information on genetic counseling, genetic testing, and effective treatment plans proactively.

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Next-Generation Sequencing - Based Germline and Somatic Genetic Testing in Triple-negative Breast Cancer

Case Medical Research ◽

10.31525/ct1-nct03920488 ◽

2019 ◽

Author(s):

Keyword(s):

Breast Cancer ◽

Genetic Testing ◽

Next Generation Sequencing ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Next Generation ◽

Generation Sequencing

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Assessment of genetic referrals and outcomes for women with triple negative breast cancer in regional cancer centres in Australia

Hereditary Cancer in Clinical Practice ◽

10.1186/s13053-021-00176-z ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Lucie G. Hallenstein ◽

Carol Sorensen ◽

Lorraine Hodgson ◽

Shelly Wen ◽

Justin Westhuyzen ◽

...

Keyword(s):

Breast Cancer ◽

Genetic Testing ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Cancer Genetics ◽

Eligibility Criteria ◽

Pathogenic Variants ◽

Genetics Services ◽

Age Of Diagnosis ◽

Over Time

Abstract Background Guidelines for referral to cancer genetics service for women diagnosed with triple negative breast cancer have changed over time. This study was conducted to assess the changing referral patterns and outcomes for women diagnosed with triple negative breast cancer across three regional cancer centres during the years 2014–2018. Methods Following ethical approval, a retrospective electronic medical record review was performed to identify those women diagnosed with triple negative breast cancer, and whether they were referred to a genetics service and if so, the outcome of that genetics assessment and/or genetic testing. Results There were 2441 women with newly diagnosed breast cancer seen at our cancer services during the years 2014–2018, of whom 237 women were diagnosed with triple negative breast cancer. Based on age of diagnosis criteria alone, 13% (31/237) of our cohort fulfilled criteria for genetic testing, with 81% (25/31) being referred to a cancer genetics service. Of this group 68% (21/31) were referred to genetics services within our regions and went on to have genetic testing with 10 pathogenic variants identified; 5x BRCA1, 4x BRCA2 and × 1 ATM:c.7271 T > G. Conclusions Referral pathways for women diagnosed with TNBC to cancer genetics services are performing well across our cancer centres. We identified a group of women who did not meet eligibility criteria for referral at their time of diagnosis, but would now be eligible, as guidelines have changed. The use of cross-discipline retrospective data reviews is a useful tool to identify patients who could benefit from being re-contacted over time for an updated cancer genetics assessment.

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Influence of Germline BRCA Genotype on the Survival of Patients with Triple-Negative Breast Cancer

Cancer Research Communications ◽

10.1158/2767-9764.crc-21-0099 ◽

2021 ◽

Vol 1 (3) ◽

pp. 140-147

Author(s):

Cynthia Villarreal-Garza ◽

Ana S. Ferrigno ◽

Alejandro Aranda-Gutierrez ◽

Paul H. Frankel ◽

Nora H. Ruel ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Point Mutations ◽

Treatment Resistance ◽

Cancer Center ◽

Breast Cancers ◽

Entire Cohort ◽

Pathogenic Variants ◽

Mutational Status

The presence of BRCA pathogenic variants (PV) in triple-negative breast cancer (TNBC) is associated with a distinctive genomic profile that makes the tumor particularly susceptible to DNA-damaging treatments. However, patients with BRCA PVs can develop treatment resistance through the appearance of reversion mutations and restored BRCA expression. As copy-number variants (CNV) could be less susceptible to reversion mutations than point mutations, we hypothesize that carriers of BRCA CNVs may have improved survival after treatment compared with carriers of other BRCA PVs or BRCA wild-type. Women diagnosed with stage I–III TNBC at ≤50 years at a cancer center in Mexico City were screened for BRCA PVs using a recurrent PV assay (HISPANEL; 77% sensitivity). Recurrence-free survival (RFS) and overall survival (OS) were compared according to the mutational status. Among 180 women, 17 (9%) were carriers of BRCA1 ex9–12del CNVs and 26 (14%) of other BRCA PVs. RFS at ten years for the whole cohort was 79.2% [95% confidence interval (CI), 72.3–84.6], with no significant differences according to mutational status. 10-year OS for the entire cohort was 85.3% (95% CI, 78.7–90.0), with BRCA CNV carriers demonstrating numerically superior OS rates other PV carriers and noncarriers (100% vs. 78.6% and 84.7%; log-rank P = 0.037 and P = 0.051, respectively). This study suggests that BRCA1 ex9–12del CNV carriers with TNBC may have a better OS, and supports the hypothesis that the genotype of BRCA PVs may influence survival by limiting treatment resistance mediated by reversion mutations among CNV carriers. Significance: Large CNV BRCA carriers in a cohort of young Mexican patients with TNBC had superior OS rates than carriers of other BRCA pathogenic variants (i.e., small indels or point mutations). We hypothesize that this is due to the resistance of CNVs to reversion mutations mediating resistance to therapy. If validated, these findings have important prognostic and clinical treatment implications for BRCA-associated breast cancers.

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