Effects of BRCA Germline Mutations on Triple-Negative Breast Cancer Prognosis

Katarzyna Pogoda; Anna Niwińska; Elżbieta Sarnowska; Dorota Nowakowska; Agnieszka Jagiełło-Gruszfeld; Janusz Siedlecki; Zbigniew Nowecki

doi:10.1155/2020/8545643

Effects of BRCA Germline Mutations on Triple-Negative Breast Cancer Prognosis

Pogoda, Katarzyna;Niwińska, Anna;Sarnowska, Elżbieta;Nowakowska, Dorota;Jagiełło-Gruszfeld, Agnieszka;Siedlecki, Janusz;Nowecki, Zbigniew 2020-01-27 00:00:00 Hindawi Journal of Oncology Volume 2020, Article ID 8545643, 10 pages https://doi.org/10.1155/2020/8545643 Research Article Effects of BRCA Germline Mutations on Triple-Negative Breast Cancer Prognosis 1 1 2 3 Katarzyna Pogoda , Anna Niwin´ska, Elz˙bieta Sarnowska, Dorota Nowakowska, 1 2 1 Agnieszka Jagiełło-Gruszfeld, Janusz Siedlecki, and Zbigniew Nowecki Department of Breast Cancer and Reconstructive Surgery, Maria Sklodowska-Curie Institute–Oncology Center, Warsaw, Poland Department of Molecular and Translational Oncology, Maria Sklodowska-Curie Institute–Oncology Center, Warsaw, Poland Genetic Counseling Unit, Cancer Prevention Center, Maria Sklodowska-Curie Institute–Oncology Center, Warsaw, Poland Correspondence should be addressed to Katarzyna Pogoda; katarzyna.pogoda@coi.pl Received 5 October 2019; Revised 5 December 2019; Accepted 13 December 2019; Published 27 January 2020 Guest Editor: Angela Toss Copyright © 2020 Katarzyna Pogoda et al. +is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Germline BRCA1 and BRCA2 mutations confer an increased lifetime risk for breast cancer and ovarian cancer. Several studies have investigated prognosis among BRCA1/2 mutation carriers and noncarriers, but the prognostic impact on outcomes of breast cancer patients has not been determined. +e aim of this study was to determine the prognosis of TNBC patients with and without BRCA1/2 germline mutation. Among 502 patients diagnosed with TNBC between 2005 and 2008, 124 patients with a strong family history of breast cancer or ovarian cancer as well as TNBC patients diagnosed under 45 years were referred to the Genetic Counseling Unit for genetic counselling and genetic tests. In 30 (24%) of them, the BRCA1/2 mutation was detected (the most common 5382insC in 18 (60%) patients). +e median follow-up of the entire group was 60 months. BRCA1/2 mutation carriers were statistically signiﬁcantly younger at TNBC diagnosis compared with nonmutation patients (41 vs 47 years, respectively). Patients with the BRCA1/2 mutation had smaller tumors (stage I: 47% vs 24.5% in noncarriers), but there was no signiﬁcant diﬀerence in the regional nodal status (58.5–63% with cN0). Contralateral breast cancer developed in 26.5% of BRCA1/2 mutation carriers and in 14% of noncarriers. Other primary cancers were also slightly more common in BRCA1/2 mutation carriers (16.5% vs 9.5%). +e performed analysis did not show any signiﬁcant diﬀerences between the groups in recurrence-free survival (p � 0.312). +ere was no signiﬁcant diﬀerence between patients with or without BRCA1/2 mutation as regards overall survival (p � 0.649) and the risk of TNBC death (p � 0.333). +e survival from detection of metastases was similar in two groups (p � 0.865). Our study demonstrated that the BRCA1 mutation does not aﬀect TNBC patients’ outcomes. 1.1. Prevalence of Breast/Ovarian Cancer. Germline BRCA1 1. Introduction and BRCA2 mutations confer an increased lifetime risk for BRCA1 and BRCA2 are tumor suppressor genes involved in breast cancer and ovarian cancer. Women with BRCA1/2 DNA damage repair, cell cycle control, gene transcription germline mutations have a higher incidence of breast cancer regulation, and apoptosis. +e common germline mutations than those without these genetic abnormalities. +e cu- of the BRCA1 gene are 5382insC, 185delAG, 3819del5, and mulative incidence of breast cancer by age 70–80 years in 4153delA and of BRCA2 are 4075delGT and 580del4 [1]. In female mutation carriers is 71.4–87% for the BRCA1 mu- the western population, about 5% of the breast cancer pa- tation and 77–88% for the BRCA2 mutation [6–8]. +e tients may carry heritable cancer susceptibility gene muta- ovarian cancer risk is 59–65% for the BRCA1 mutation and 34.5–37% for the BRCA2 mutation [6, 8]. +e high lifetime tions, with BRCA1 being the most common mutation [2]. +e mutation rate can be higher in Ashkenazi Jews [3, 4]. risk of breast and ovarian cancers in BRCA1/2 carriers is Interestingly, BRCA1/2 mutation rates in Asians are lower crucial for counselling, intensive breast and ovarian than those in whites [5]. screening (annual MRI commenced from the age of 25 with 2 Journal of Oncology the additional annual mammography from the age of 30, 6- (185delAG), c.676delT (p.Cys226Valfs), c.1687C>T monthly ovarian cancer screening with transvaginal ultra- (p.Gln563Ter), c.3756_3759delGTCT (3875del4), c.4035delA sound, and Ca125 serum measure started at the age of 30), (4153delA), c.5251C>T (5370C>T), and c.5345G>A and risk-reducing surgery (bilateral salpingo-oophorectomy (p.Trp1782X) and BRCA2 gene: c.658_659del GT (p.Val220fs), and bilateral risk-reducing mastectomy including skin- c.5946delT (6174delT), c.9371A>T (p.Asn3124Ile), and sparing and nipple-sparing mastectomy) [9, 10]. c.5744C>T (C5972T). Characteristics of the whole group of 502 Compared to BRCA2 carriers and noncarriers, BRCA1- TNBC patients and 124 patients in whom genetic tests were associated breast cancers are often high-grade and poorly performed are presented in Tables 1 and 2. +e Ki-67 ex- diﬀerentiated inﬁltrating ductal carcinoma and are more pression and vimentin expression were conducted additionally often triple-negative with higher expressions of cytokeratin due to the fact that, in the analyzed period of time, these 5/6, cyclin E, and p53. Patients with BRCA1-associated markers were not assessed as standard practice (vimentin still breast cancers are younger than those with the BRCA2 remains as an experimental biomarker, expressed more often in mutation and those without mutation [11, 12]. mesenchymal tumors). +e decisions on therapy were made regardless of the BRCA1/2 mutation status. 1.2. Prognosis. Several studies have investigated prognosis among BRCA1/2 mutation carriers and noncarriers, but the 3.1. Statistical Analysis. Univariate analysis was performed prognostic impact on outcomes of breast cancer patients has in order to compare patient and tumor characteristics (age at not been deﬁnitely determined. It is controversial whether diagnosis, clinical stage, HER2 expression, histological grade BRCA1/2 mutations in breast cancer are associated with G, Ki-67 expression, and vimentin expression) as well as therapy (type of surgery, radiotherapy, and (neo)adjuvant poor prognosis. Some studies revealed that BRCA1/2 mu- tation carriers with breast cancer had worse overall survival chemotherapy) depending on the BRCA1/2 mutation status. R Development Core Team (R 3.1.3., 2009) software was (OS) than noncarriers [13–15], others showed no diﬀerence [16–20], and some studies indicated that BRCA1/2 mutation used for these analyses. carriers had better survival than noncarriers [21–23]. Dif- +e following deﬁnitions of events were used: ferences could be partly the result of the analysis of diﬀerent (i) RFS—time from TNBC diagnosis to recurrence ethnic populations (Ashkenazi Jewish population [24], (ii) OS—time from TNBC diagnosis to death from any central-eastern population [15], western population [19], or cause Asian population [20, 25]), small study group with muta- tions, variations in mutation assay techniques, mutation (iii) Breast cancer-speciﬁc survival (BCSS)—time from types, cancer treatment modalities, or length of follow-up. TNBC diagnosis to death from breast cancer Among all biological subtypes of breast cancer, triple- (iv) Survival from dissemination—time from recurrence negative breast cancer (TNBC) is more likely to harbor a to death from any cause germline BRCA1/2 mutation, with reported prevalence rates +en, RFS, OS, and survival from dissemination of the varying from about 10% to 20% [20, 22, 26, 27]. +e eﬀect of disease in both groups were assessed. Additionally, risk of the BRCA1/2 mutation on the prognosis in TNBC patients breast cancer death using the competing risk method was has not been well examined, with divergent ﬁndings re- evaluated. Finally, the BRCA1/2 mutation was assessed as ported in the previous studies [18, 20, 22, 28–30]. one of the seven prognostic factors for recurrence and survival in multivariate analysis using the multistep Cox 2. Aim model. +e other prognostic factors in the Cox model were age at diagnosis, TNM stage (I, II, or III), Ki-67 expression, +e aim of this study was to determine the prognosis of TNBC patients with and without BRCA1/2 germline vimentin expression, histological grade G (G1, G2, or G3), and histological type (no special type—NST or others). mutation. 3. Materials and Methods 4. Results Five hundred two consecutive TNBC patients treated at the Finally, 124 (25%) out of 502 TNBC patients had undergone Department of Breast Cancer and Reconstructive Surgery, genetic counselling with BRCA1/2 mutation tests and were Maria Skłodowska-Curie Institute–Cancer Center (MSCI), included for further analysis. In 30 (24%) of them, the Warsaw, Poland, between 2005 and 2008, were selected and BRCA1/2 mutation was detected. Only in one case, the analyzed to assess risk factors of recurrence, recurrence-free mutation of the BRCA2 gene was found, and for the BRCA1 survival (RFS), and OS. Among them, 124 patients with a gene, 29 mutated cases were detected. +e following BRCA1 strong family history of breast cancer or ovarian cancer as well mutations were found: c.5266dupC (5382insC) in 18 pa- as TNBC patients diagnosed under 45 years were referred to tients, c.181T>G (C61G, 300T>G) in 5 patients, the Genetic Counseling Unit of Cancer Prevention Department c.3700_3704delGTAAA (3819del5) in 2 patients, and in MSCI, Warsaw, for genetic counselling and genetic tests. +e c.5251C>T (5370C>T), c.5345G>A (p.Trp1782X), patients were tested for the following BRCA1/2 mutations: c.3756_3759delGTCT (3875del4), and c.68_69delAG BRCA1 gene: c.5266dupC (5382insC), c.181T>G (C61G, (185delAG) in 1 patient each, respectively. One patient 300T>G), c.3700_3704delGTAAA (3819del5), c.68_69delAG harbored BRCA2 gene mutation c.5744C>T (C5972T). +e Journal of Oncology 3 Table 1: Characteristics of 502 TNBC patients. Factor Rate (%) Number of patients 502 100 Age at diagnosis (years) Median 55 Mean 56 Range 24–98 Clinical staging (cTNM) I 97 19.5 II 246 49 III 132 26 IV 27 5.5 Initial clinical tumor staging cT0 7 1 cT1 111 22 cT2 248 49.5 cT3 58 12 cT4 76 15 No available data 2 0.5 Initial clinical node staging cN0 243 48 cN1 180 36 cN2 58 11.5 cN3 19 4 No available data 2 0.5 HER2 expression 0 or 1+ 431 86 2+, FISH negative 71 14 Histological type NST 416 83 Lobular 25 5 Medullar 11 2 Apocrine 11 2 Metaplastic 20 4 Others 20 4 1 21 4 2 165 33 3 310 62 No available data 6 1 Ki-67 expression <14% 140 28 14–30% 183 36.5 >30% 133 26.5 No available data 46 9 Vimentin expression assessed Yes 443 88 No 59 12 Vimentin Positive 71/443 16 Negative 372/443 84 Contralateral breast cancer 41 8 Other primary cancer (other than contralateral breast cancer) 45 9 FISH: ﬂuorescence in situ hybridization. comparison between BRCA1/2 mutation carriers and non- respectively). Patients with the BRCA1/2 mutation had carriers is presented in Table 2. +e median follow-up of the smaller tumors (stage I: 47% vs 24.5% in noncarriers), but entire group was 60 months. BRCA1/2 mutation carriers there was no signiﬁcant diﬀerence in the regional nodal were statistically signiﬁcantly younger at TNBC diagnosis status (58.5–63% with cN0). +e most common histological compared with nonmutation patients (41 vs 47 years, type was NST in both groups with a similar rate of medullar 4 Journal of Oncology Table 2: Characteristics of 124 TNBC patients assessed for BRCA1/2 mutations. Patients tested for BRCA mutations p value (BRCA-positive vs BRCA- Factor BRCA Rate BRCA Rate negative) noncarriers (%) carriers (%) Number of patients 94 100 30 100 Age at diagnosis (years) Median 49 40 Mean 47.5 41.4 0.0115 Range 25–67 24–76 Clinical staging (cTNM) I 23 24.5 14 47 II 51 54 13 43 0.0006 III 19 20 2 7 IV 1 <0.5 1 3 Initial clinical tumor staging cT0 0 0 0 0 cT1 28 30 16 53 cT2 56 59.5 9 30 0.0004 cT3 4 4 2 7 cT4 6 6.5 3 10 No available data 0 0 0 0 Initial clinical node staging cN0 55 58.5 19 63 cN1 27 28.5 10 33 cN2 9 9.5 1 4 0.1063 cN3 3 3.5 0 0 No available data 0 0 0 0 HER2 expression 0 or 1+ 79 84 29 97 0.0091 2+, FISH negative 15 16 1 3 Histological type NST 80 21 70 Lobular 5 85 1 3.5 Medullar 5 5.5 1 3.5 0.0023 Apocrine 2 5.5 1 3.5 Metaplastic 2 2 2 6 Others 0 2 4 13.5 1 0 0 2 6.5 2 29 30 12 40 0.0065 3 64 68 16 53.5 No available data 1 2 0 0 Ki-67 expression <14% 26 27.5 5 16.5 14–30% 29 31 10 33.5 0.0761 >30% 28 30 13 43.5 No available data 11 11.5 2 6.5 Vimentin expression assessed Yes 82 87 26 86.5 0.8361 No 12 13 4 13.5 Vimentin Positive 14 15 8 26.5 0.0372 Negative 68 85 18 73.5 Contralateral breast cancer 13 14 8 26.5 0.0228 Other primary cancer (other than contralateral 9 9.5 5 16.5 0.1475 breast cancer) FISH: ﬂuorescence in situ hybridization. Journal of Oncology 5 cancer (3.5–5.5%). Noncarriers had more often G3 tumors. 5.1. All Biological Types of Breast Cancer. +e meta-analysis Contralateral breast cancer developed in 26.5% of BRCA1/2 of 11 studies performed by Lee et al. revealed that patients mutation carriers and in 14% of noncarriers. In both groups, with breast cancer and BRCA1 mutation had worse OS almost half contralateral breast cancers developed before compared to noncarriers (HR � 1.92). +e BRCA2 mutation TNBC diagnosis. Other primary cancers were also slightly did not aﬀect survival in patients with breast cancer more common in BRCA1/2 mutation carriers (16.5% vs (HR � 1.30) [31]. 9.5%). Almost all cases occurred after TNBC diagnosis in In meta-analysis by Zhong et al. [32], based on 13 studies both groups (only 2 cases of lymphoma and one ovarian with 10 016 women with breast cancer, concerning breast cancer developed before TNBC). +e summary of these cancer survival, the BRCA1 mutation carriers had worse OS results is presented in Table 2. than noncarriers (HR � 1.5, p � 0.009) but were not sig- In 72 patients (58% of all TNBC), the primary operation niﬁcantly diﬀerent from noncarriers in terms of progres- was performed. In other 47 (38%) patients, surgery was sion-free survival (HR � 1.35, p � 0.09). carried out after neoadjuvant chemotherapy. Breast-con- In other meta-analysis performed by Zhu et al. [3], based on 34 studies, event-free survival (EFS), OS, and BCSS were serving surgery was more common in BRCA1/2 mutation carriers (41.5% vs 33.5%). Adjuvant chemotherapy was compared in three groups of breast cancer patients: BRCA1 performed in 87 patients (90% after primary surgery). carriers, BRCA2 carriers, and BRCA1/2 noncarriers. In Overall, (neo)adjuvant chemotherapy was performed in a patients with BRCA1 and BRCA2 mutations, OS was worse similar percentage of patients with or without BRCA1/2 than that in patients without mutation (p< 0.001 and mutation. +e summary of patient therapy is presented in p � 0.034, respectively) but did not translate into poor BCSS Table 3. (p � 0.448 and p � 0.401, respectively) or EFS (p � 0.438 We compared RFS, OS, risk of breast cancer death, and and p � 0.558, respectively) [3]. +e BRCA1 mutation was survival from distant metastases in BRCA1/2 carriers and signiﬁcantly associated with worse OS in studies conducted noncarriers. +e performed analysis did not show any in Europe (p< 0.001) and studies assessing patients diag- signiﬁcant diﬀerences between the groups in RFS nosed before 1995 (p< 0.007). +e POSH prospective cohort study analyzed patients (p � 0.312), also after taking into account the clinical stage of TNBC (in patients in the following stages: I: p � 1.0, II: with young-onset breast cancer (≤40 years) regarding the p � 0.454, and III: p � 0.197) or (neo)adjuvant chemo- BRCA1/2 mutation status [33]. Recently published results therapy (p> 0.05). +e risk of the recurrence depending on indicated no signiﬁcant diﬀerence in OS or distant disease- the BRCA1/2 mutation status is shown in Figure 1. +ere was free survival between patients carrying BRCA1/2 mutations no signiﬁcant diﬀerence between patients with or without and patients without those mutations after a diagnosis of BRCA1/2 mutation regarding overall survival (p � 0.649). breast cancer. +e BRCA1/2 mutation was not a prognostic factor of pa- A study by Wang et al. performed on the Chinese cohort tient survival. +e results are presented in Figure 2. +e risk revealed that patients with BRCA1/2 mutations had worse of TNBC death did not diﬀer signiﬁcantly in both groups survival outcomes than noncarriers [25]. BRCA1/2 mutation (Figure 3). carriers were more likely to have lymph node involvement at In 13% (4/30) of BRCA1/2 mutation patients and in 21% initial diagnosis than noncarriers [25]. In our study, we did (20/94) of noncarriers, the recurrence of the disease was not observe these kinds of relations. detected. In both groups, there was one patient with primary metastatic TNBC. +ere was no signiﬁcant diﬀerence in survival from detection of metastases between these two 5.2. Triple-Negative Breast Cancer. Studies that have eval- uated the prognostic role of the BRCA1/2 mutation in pa- groups (p � 0.865). +e results are presented in Figure 4. Among seven variables taken in multivariate analysis, tients with TNBC have shown inconclusive results, but the newest and larger ones are in line with our study. TNM stage was the only factor signiﬁcantly inﬂuencing recurrence and death. +ere was no correlation between RFS In the study performed by Yadav et al. [34], 266 TNBC patients had undergone BRCA1/2 mutation tests. In 27% of or OS and other analyzed risk factors, including the BRCA1/ them, BRCA1/2 mutations were detected. No statistically 2 germline mutation. +e results are shown in Tables 4 and 5. signiﬁcant diﬀerence was found in locoregional recurrence, distant recurrence, RFS, and OS between the breast cancer 5. Discussion patients with and without BRCA1/2 mutations. 5-year OS for BRCA1/2-positive and BRCA1/2-negative breast cancer Our study showed that the outcome of TNBC patients did patients was 83% and 90% and 5-year RFS was 83% and 80%, not diﬀer depending on the BRCA mutation status. We respectively. +e diﬀerences were not statistically signiﬁcant aimed to clarify the prognostic value of BRCA1/2 mutations on breast cancer-speciﬁc outcomes after conventional [34]. In the study by Gonzales-Angulo et al. [22], based on 77 treatment. In our study, RFS, OS, and risk of death from TNBC were similar between patients with breast cancer and TNBC patients, RFS was better for patients with the BRCA1/ 2 mutation and OS was similar between carriers and BRCA1 germline mutation and noncarriers. Because of the noncarriers. fact that among our patients with BRCA1/2 mutations only In another study, Maksimenko et al. [30] compared the one had BRCA2 mutation, the results and discussion con- outcomes of 78 TNBC patients without BRCA1 mutation cern about patients with breast cancer and BRCA1 mutation. 6 Journal of Oncology Table 3: +erapy of 124 TNBC patients assessed for BRCA1/2 mutations. Patients tested for BRCA mutations Type of therapy p value (BRCA-positive vs BRCA-negative) BRCA noncarriers Rate (%) BRCA carriers Rate (%) Number of patients 94 100 30 100 Surgery Yes 90 96 29 97 0.7004 No 4 4 1 3 Type of surgery Mastectomy 60/90 66.5 17/29 58.5 0.2438 Breast-conserving surgery 30/90 33.5 12/29 41.5 Radiotherapy Yes 55 58.5 17 56.5 0.7751 No 39 41.5 13 43.5 Radiotherapy After mastectomy 27/55 49 5/17 29.5 0.0044 After breast-conserving surgery 28/55 51 12/17 70.5 Neoadjuvant chemotherapy Yes 20 21.5 4 13.5 0.0940 No 74 78.5 26 86.5 Regimens in neoadjuvant chemotherapy AT⟶CMF 5/20 25 1/4 25 Anthracycline + taxane 9/20 45 2/4 50 <0.0001 Anthracycline 5/20 5 1/4 25 Others 1/20 25 0 0 Adjuvant chemotherapy Yes 64 68 23 76.5 0.1541 No 30 32 7 23.5 Regimens in adjuvant chemotherapy Anthracycline (AC) 41/64 64 12/23 52 FEC/FAC 11/64 17.5 4/23 17.5 Anthracycline + taxane 8/64 12.5 5/23 21.5 0.0574 CMF 2/64 3 0 0 Taxane 2/64 3 2/23 9 0 20 40 60 80 100 120 140 Time (months) BRCA mutation Negative Positive RFS Median RFS BRCA mutation n p (months) 12 months 24 months 36 months 60 months 120 months Negative 93 96.6% 86.0% 83.6% 77.2% 75.3% Not reached p = 0.312 Positive 29 96.4% 92.9% 85.7% 85.7% 85.7% Not reached Figure 1: Risk of recurrence in TNBC patients depending on the BRCA mutation status. RFS (%) Journal of Oncology 7 0 20 40 60 80 100 120 140 Time (months) BRCA mutation Negative Positive OS Median OS BRCA mutation n p (months) 12 months 24 months 36 months 60 months 120 months Negative 93 97.8% 90.8% 86.1% 78.5% 62.8% Not reached p = 0.649 Positive 29 100% 93.5% 90.3% 86.7% 70.8%Not reached Figure 2: Risk of death in TNBC patients depending on the BRCA mutation status. 0 20406080 100 120 Time (months) BRCA mutation Negative Positive Cumulative probability of death from TNBC Median OS BRCA mutation n p from TNBC 12 months 24 months 36 months 60 months 120 months (months) Negative 93 2.2% 8.0% 11.6% 16.6% 25.3% Not reached p = 0.333 Positive 29 0.0% 6.4% 9.7% 9.7% 13.3% Not reached Figure 3: Relationship between the presence of the BRCA1/2 mutation and the risk of death due to TNBC. OS (%) Cumulative survival from TNBC (%) 8 Journal of Oncology 0 20406080 100 Time (months) BRCA mutation Negative Positive Median survival Survival from metastasis development from metastasis BRCA mutation n p development 12 months 24 months 36 months 60 months (months) Negative 21 52.4% 16.3% 16.3% 10.9% 12.85 p = 0.865 Positive 5 60.0% 40.0% 0.0% 0.0% 12.23 Figure 4: Survival time counted from relapse depending on the BRCA1/2 mutation status. Table 4: Multivariate analysis: ﬁnal model for RFS. estimated. +e authors found that BRCA1 mutation carriers had a 30% higher risk of dying than BRCA1-negative/spo- Factor HR 95% CI p radic cases (OS), but they did not ﬁnd association between Clinical stage: I or II Reference BRCA1 and the risk of death from breast cancer (BCSS). Clinical stage: III 43.26 2.13 880.64 0.014 Contrary to patients with all subtypes of breast cancer, 1748 patients with TNBC and BRCA1/2 mutations had better OS than BRCA1/2-negative ones (HR � 0.49) [24]. +e risk of Table 5: Multivariate analysis: ﬁnal model for OS. recurrence in TNBC was not statistically diﬀerent between BRCA1/2 carriers and BRCA1/2 noncarriers (p � 0.82). Factor HR 95% CI p BCSS and DMFS of BRCA1 mutation carriers did not diﬀer Clinical stage: I Reference from those of BRCA1-negative TNBC patients (p � 0.76 and Clinical stage: II 2.359 1.385 4.016 0.002 p � 0.65, respectively) [24]. Clinical stage: III 8.353 4.918 14.188 <0.001 In the present study, all investigated TNBC cases were diagnosed and treated in one breast cancer department. +e with those of 38 TNBC patients with the BRCA1 mutation. used methods did not diﬀer depending on the BRCA1/2 mutation status, and patients had a long time of follow-up +e BCSS and distant recurrence were signiﬁcantly lower in the BRCA1-positive patients. In 4 other larger studies, there (up to 10 years). Nowadays, new drugs such as poly(- adenosine diphosphate-ribose) polymerase (PARP) inhibi- was no diﬀerence found in recurrence and survival between TNBC carriers and noncarriers of BRCA1/2 mutations tors (olaparib and talazoparib) are dedicated to metastatic BRCA1/2-positive TNBC as well as immunotherapy for [18, 20, 28, 29]. A meta-analysis of 11 papers performed by Xie et al. also revealed that RFS and OS in TNBC patients PDL-1-positive metastatic TNBC [35–37]. +ese drugs can inﬂuence the survival of BRCA1/2 carriers with TNBC in the with and without BRCA1/2 mutations did not diﬀer [20]. Baretta et al. [24] performed a meta-analysis concerning future. In the analyzed cohort with metastatic disease, the the relation between BRCA1/2 mutation and prognosis of survival did not depend on the BRCA1/2 mutation status. In breast cancer based on 105 220 breast cancer patients in- contrast, Larson et al. showed that BRCA carriers with cluding 3588 (3.4%) BRCA1/2 mutation carriers. OS, BCSS, metastatic TNBC had clinically signiﬁcant improved OS at 3 years compared to patients without BRCA mutations (3-year RFS, and distant metastasis-free survival (DMFS) were Survival from metastases (%) Journal of Oncology 9 [3] Y. Zhu, J. Wu, C. Zhang et al., “BRCA mutations and survival OS of 63% vs 28%). In that study also, no patients received in breast cancer: an updated systematic review and meta- treatment with the PARP inhibitor [38]. analysis,” Oncotarget, vol. 7, pp. 70113–70127, 2016. [4] E. Warner, W. Foulkes, P. Goodwin et al., “Prevalence and 6. Limitations of the Study penetrance of BRCA1 and BRCA2 gene mutations in unse- lected Ashkenazi Jewish women with breast cancer,” JNCI +e retrospective nature of the study and a small number of Journal of the National Cancer Institute, vol. 91, no. 14, recurrences or deaths in patients who had undergone genetic pp. 1241–1247, 1999. tests are two main limitations of this study. [5] J. Zhang, R. Pei, Z. Pang et al., “Prevalence and character- Out of 502 consecutive TNBC patients referred to MSCI ization of BRCA1 and BRCA2 germline mutations in Chinese between the years 2005 and 2008, only 124 (25%) patients women with familial breast cancer,” Breast Cancer Research and Treatment, vol. 132, no. 2, pp. 421–428, 2012. underwent genetic tests for the BRCA1/2 mutation. From [6] D. G. Evans, A. Shenton, E. Woodward, F. Lalloo, A. Howell, them, the BRCA1/2 mutation was found only in 30 cases, and E. R. Maher, “Penetrance estimates for BRCA1 and which gives 6% (30/502) BRCA1/2 carriers among 502 BRCA2 based on genetic testing in a clinical cancer genetics TNBC patients. According to the current NCCN guideline service setting: risks of breast/ovarian cancer quoted should and ESMO recommendations, 65% of all TNBC patients reﬂect the cancer burden in the family,” BMC Cancer, vol. 8, from our analysis met the genetic test criteria solely by their no. 1, 2008. age at diagnosis of TNBC (up to 60 years); therefore, the tests [7] D. Ford, D. F. Easton, M. Stratton et al., “Genetic hetero- should be performed [10, 39]. +is number might be even geneity and penetrance analysis of the BRCA1 and BRCA2 higher considering other criteria such as a strong family genes in breast cancer families. +e breast cancer linkage history of breast/ovarian cancer. In the years 2005–2008, consortium,” American Journal of Human Genetics, vol. 62, genetic tests were oﬀered at our institution only for patients no. 62, pp. 676–689, 1998. with a strong family history of breast/ovarian cancer and for [8] D. M. Van der Kolk, G. H. de Bock, B. K. 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Yadav et al., “Impact of BRCA mutation status on survival of women with triple-negative http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Oncology Hindawi Publishing Corporation http://www.deepdyve.com/lp/hindawi-publishing-corporation/effects-of-brca-germline-mutations-on-triple-negative-breast-cancer-JlS7Dos5NA

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Publisher: Hindawi Publishing Corporation
Copyright: Copyright © 2020 Katarzyna Pogoda et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ISSN: 1687-8450
eISSN: 1687-8469
DOI: 10.1155/2020/8545643
Publisher site: See Article on Publisher Site

Abstract

Hindawi Journal of Oncology Volume 2020, Article ID 8545643, 10 pages https://doi.org/10.1155/2020/8545643 Research Article Effects of BRCA Germline Mutations on Triple-Negative Breast Cancer Prognosis 1 1 2 3 Katarzyna Pogoda , Anna Niwin´ska, Elz˙bieta Sarnowska, Dorota Nowakowska, 1 2 1 Agnieszka Jagiełło-Gruszfeld, Janusz Siedlecki, and Zbigniew Nowecki Department of Breast Cancer and Reconstructive Surgery, Maria Sklodowska-Curie Institute–Oncology Center, Warsaw, Poland Department of Molecular and Translational Oncology, Maria Sklodowska-Curie Institute–Oncology Center, Warsaw, Poland Genetic Counseling Unit, Cancer Prevention Center, Maria Sklodowska-Curie Institute–Oncology Center, Warsaw, Poland Correspondence should be addressed to Katarzyna Pogoda; katarzyna.pogoda@coi.pl Received 5 October 2019; Revised 5 December 2019; Accepted 13 December 2019; Published 27 January 2020 Guest Editor: Angela Toss Copyright © 2020 Katarzyna Pogoda et al. +is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Germline BRCA1 and BRCA2 mutations confer an increased lifetime risk for breast cancer and ovarian cancer. Several studies have investigated prognosis among BRCA1/2 mutation carriers and noncarriers, but the prognostic impact on outcomes of breast cancer patients has not been determined. +e aim of this study was to determine the prognosis of TNBC patients with and without BRCA1/2 germline mutation. Among 502 patients diagnosed with TNBC between 2005 and 2008, 124 patients with a strong family history of breast cancer or ovarian cancer as well as TNBC patients diagnosed under 45 years were referred to the Genetic Counseling Unit for genetic counselling and genetic tests. In 30 (24%) of them, the BRCA1/2 mutation was detected (the most common 5382insC in 18 (60%) patients). +e median follow-up of the entire group was 60 months. BRCA1/2 mutation carriers were statistically signiﬁcantly younger at TNBC diagnosis compared with nonmutation patients (41 vs 47 years, respectively). Patients with the BRCA1/2 mutation had smaller tumors (stage I: 47% vs 24.5% in noncarriers), but there was no signiﬁcant diﬀerence in the regional nodal status (58.5–63% with cN0). Contralateral breast cancer developed in 26.5% of BRCA1/2 mutation carriers and in 14% of noncarriers. Other primary cancers were also slightly more common in BRCA1/2 mutation carriers (16.5% vs 9.5%). +e performed analysis did not show any signiﬁcant diﬀerences between the groups in recurrence-free survival (p � 0.312). +ere was no signiﬁcant diﬀerence between patients with or without BRCA1/2 mutation as regards overall survival (p � 0.649) and the risk of TNBC death (p � 0.333). +e survival from detection of metastases was similar in two groups (p � 0.865). Our study demonstrated that the BRCA1 mutation does not aﬀect TNBC patients’ outcomes. 1.1. Prevalence of Breast/Ovarian Cancer. Germline BRCA1 1. Introduction and BRCA2 mutations confer an increased lifetime risk for BRCA1 and BRCA2 are tumor suppressor genes involved in breast cancer and ovarian cancer. Women with BRCA1/2 DNA damage repair, cell cycle control, gene transcription germline mutations have a higher incidence of breast cancer regulation, and apoptosis. +e common germline mutations than those without these genetic abnormalities. +e cu- of the BRCA1 gene are 5382insC, 185delAG, 3819del5, and mulative incidence of breast cancer by age 70–80 years in 4153delA and of BRCA2 are 4075delGT and 580del4 [1]. In female mutation carriers is 71.4–87% for the BRCA1 mu- the western population, about 5% of the breast cancer pa- tation and 77–88% for the BRCA2 mutation [6–8]. +e tients may carry heritable cancer susceptibility gene muta- ovarian cancer risk is 59–65% for the BRCA1 mutation and 34.5–37% for the BRCA2 mutation [6, 8]. +e high lifetime tions, with BRCA1 being the most common mutation [2]. +e mutation rate can be higher in Ashkenazi Jews [3, 4]. risk of breast and ovarian cancers in BRCA1/2 carriers is Interestingly, BRCA1/2 mutation rates in Asians are lower crucial for counselling, intensive breast and ovarian than those in whites [5]. screening (annual MRI commenced from the age of 25 with 2 Journal of Oncology the additional annual mammography from the age of 30, 6- (185delAG), c.676delT (p.Cys226Valfs), c.1687C>T monthly ovarian cancer screening with transvaginal ultra- (p.Gln563Ter), c.3756_3759delGTCT (3875del4), c.4035delA sound, and Ca125 serum measure started at the age of 30), (4153delA), c.5251C>T (5370C>T), and c.5345G>A and risk-reducing surgery (bilateral salpingo-oophorectomy (p.Trp1782X) and BRCA2 gene: c.658_659del GT (p.Val220fs), and bilateral risk-reducing mastectomy including skin- c.5946delT (6174delT), c.9371A>T (p.Asn3124Ile), and sparing and nipple-sparing mastectomy) [9, 10]. c.5744C>T (C5972T). Characteristics of the whole group of 502 Compared to BRCA2 carriers and noncarriers, BRCA1- TNBC patients and 124 patients in whom genetic tests were associated breast cancers are often high-grade and poorly performed are presented in Tables 1 and 2. +e Ki-67 ex- diﬀerentiated inﬁltrating ductal carcinoma and are more pression and vimentin expression were conducted additionally often triple-negative with higher expressions of cytokeratin due to the fact that, in the analyzed period of time, these 5/6, cyclin E, and p53. Patients with BRCA1-associated markers were not assessed as standard practice (vimentin still breast cancers are younger than those with the BRCA2 remains as an experimental biomarker, expressed more often in mutation and those without mutation [11, 12]. mesenchymal tumors). +e decisions on therapy were made regardless of the BRCA1/2 mutation status. 1.2. Prognosis. Several studies have investigated prognosis among BRCA1/2 mutation carriers and noncarriers, but the 3.1. Statistical Analysis. Univariate analysis was performed prognostic impact on outcomes of breast cancer patients has in order to compare patient and tumor characteristics (age at not been deﬁnitely determined. It is controversial whether diagnosis, clinical stage, HER2 expression, histological grade BRCA1/2 mutations in breast cancer are associated with G, Ki-67 expression, and vimentin expression) as well as therapy (type of surgery, radiotherapy, and (neo)adjuvant poor prognosis. Some studies revealed that BRCA1/2 mu- tation carriers with breast cancer had worse overall survival chemotherapy) depending on the BRCA1/2 mutation status. R Development Core Team (R 3.1.3., 2009) software was (OS) than noncarriers [13–15], others showed no diﬀerence [16–20], and some studies indicated that BRCA1/2 mutation used for these analyses. carriers had better survival than noncarriers [21–23]. Dif- +e following deﬁnitions of events were used: ferences could be partly the result of the analysis of diﬀerent (i) RFS—time from TNBC diagnosis to recurrence ethnic populations (Ashkenazi Jewish population [24], (ii) OS—time from TNBC diagnosis to death from any central-eastern population [15], western population [19], or cause Asian population [20, 25]), small study group with muta- tions, variations in mutation assay techniques, mutation (iii) Breast cancer-speciﬁc survival (BCSS)—time from types, cancer treatment modalities, or length of follow-up. TNBC diagnosis to death from breast cancer Among all biological subtypes of breast cancer, triple- (iv) Survival from dissemination—time from recurrence negative breast cancer (TNBC) is more likely to harbor a to death from any cause germline BRCA1/2 mutation, with reported prevalence rates +en, RFS, OS, and survival from dissemination of the varying from about 10% to 20% [20, 22, 26, 27]. +e eﬀect of disease in both groups were assessed. Additionally, risk of the BRCA1/2 mutation on the prognosis in TNBC patients breast cancer death using the competing risk method was has not been well examined, with divergent ﬁndings re- evaluated. Finally, the BRCA1/2 mutation was assessed as ported in the previous studies [18, 20, 22, 28–30]. one of the seven prognostic factors for recurrence and survival in multivariate analysis using the multistep Cox 2. Aim model. +e other prognostic factors in the Cox model were age at diagnosis, TNM stage (I, II, or III), Ki-67 expression, +e aim of this study was to determine the prognosis of TNBC patients with and without BRCA1/2 germline vimentin expression, histological grade G (G1, G2, or G3), and histological type (no special type—NST or others). mutation. 3. Materials and Methods 4. Results Five hundred two consecutive TNBC patients treated at the Finally, 124 (25%) out of 502 TNBC patients had undergone Department of Breast Cancer and Reconstructive Surgery, genetic counselling with BRCA1/2 mutation tests and were Maria Skłodowska-Curie Institute–Cancer Center (MSCI), included for further analysis. In 30 (24%) of them, the Warsaw, Poland, between 2005 and 2008, were selected and BRCA1/2 mutation was detected. Only in one case, the analyzed to assess risk factors of recurrence, recurrence-free mutation of the BRCA2 gene was found, and for the BRCA1 survival (RFS), and OS. Among them, 124 patients with a gene, 29 mutated cases were detected. +e following BRCA1 strong family history of breast cancer or ovarian cancer as well mutations were found: c.5266dupC (5382insC) in 18 pa- as TNBC patients diagnosed under 45 years were referred to tients, c.181T>G (C61G, 300T>G) in 5 patients, the Genetic Counseling Unit of Cancer Prevention Department c.3700_3704delGTAAA (3819del5) in 2 patients, and in MSCI, Warsaw, for genetic counselling and genetic tests. +e c.5251C>T (5370C>T), c.5345G>A (p.Trp1782X), patients were tested for the following BRCA1/2 mutations: c.3756_3759delGTCT (3875del4), and c.68_69delAG BRCA1 gene: c.5266dupC (5382insC), c.181T>G (C61G, (185delAG) in 1 patient each, respectively. One patient 300T>G), c.3700_3704delGTAAA (3819del5), c.68_69delAG harbored BRCA2 gene mutation c.5744C>T (C5972T). +e Journal of Oncology 3 Table 1: Characteristics of 502 TNBC patients. Factor Rate (%) Number of patients 502 100 Age at diagnosis (years) Median 55 Mean 56 Range 24–98 Clinical staging (cTNM) I 97 19.5 II 246 49 III 132 26 IV 27 5.5 Initial clinical tumor staging cT0 7 1 cT1 111 22 cT2 248 49.5 cT3 58 12 cT4 76 15 No available data 2 0.5 Initial clinical node staging cN0 243 48 cN1 180 36 cN2 58 11.5 cN3 19 4 No available data 2 0.5 HER2 expression 0 or 1+ 431 86 2+, FISH negative 71 14 Histological type NST 416 83 Lobular 25 5 Medullar 11 2 Apocrine 11 2 Metaplastic 20 4 Others 20 4 1 21 4 2 165 33 3 310 62 No available data 6 1 Ki-67 expression <14% 140 28 14–30% 183 36.5 >30% 133 26.5 No available data 46 9 Vimentin expression assessed Yes 443 88 No 59 12 Vimentin Positive 71/443 16 Negative 372/443 84 Contralateral breast cancer 41 8 Other primary cancer (other than contralateral breast cancer) 45 9 FISH: ﬂuorescence in situ hybridization. comparison between BRCA1/2 mutation carriers and non- respectively). Patients with the BRCA1/2 mutation had carriers is presented in Table 2. +e median follow-up of the smaller tumors (stage I: 47% vs 24.5% in noncarriers), but entire group was 60 months. BRCA1/2 mutation carriers there was no signiﬁcant diﬀerence in the regional nodal were statistically signiﬁcantly younger at TNBC diagnosis status (58.5–63% with cN0). +e most common histological compared with nonmutation patients (41 vs 47 years, type was NST in both groups with a similar rate of medullar 4 Journal of Oncology Table 2: Characteristics of 124 TNBC patients assessed for BRCA1/2 mutations. Patients tested for BRCA mutations p value (BRCA-positive vs BRCA- Factor BRCA Rate BRCA Rate negative) noncarriers (%) carriers (%) Number of patients 94 100 30 100 Age at diagnosis (years) Median 49 40 Mean 47.5 41.4 0.0115 Range 25–67 24–76 Clinical staging (cTNM) I 23 24.5 14 47 II 51 54 13 43 0.0006 III 19 20 2 7 IV 1 <0.5 1 3 Initial clinical tumor staging cT0 0 0 0 0 cT1 28 30 16 53 cT2 56 59.5 9 30 0.0004 cT3 4 4 2 7 cT4 6 6.5 3 10 No available data 0 0 0 0 Initial clinical node staging cN0 55 58.5 19 63 cN1 27 28.5 10 33 cN2 9 9.5 1 4 0.1063 cN3 3 3.5 0 0 No available data 0 0 0 0 HER2 expression 0 or 1+ 79 84 29 97 0.0091 2+, FISH negative 15 16 1 3 Histological type NST 80 21 70 Lobular 5 85 1 3.5 Medullar 5 5.5 1 3.5 0.0023 Apocrine 2 5.5 1 3.5 Metaplastic 2 2 2 6 Others 0 2 4 13.5 1 0 0 2 6.5 2 29 30 12 40 0.0065 3 64 68 16 53.5 No available data 1 2 0 0 Ki-67 expression <14% 26 27.5 5 16.5 14–30% 29 31 10 33.5 0.0761 >30% 28 30 13 43.5 No available data 11 11.5 2 6.5 Vimentin expression assessed Yes 82 87 26 86.5 0.8361 No 12 13 4 13.5 Vimentin Positive 14 15 8 26.5 0.0372 Negative 68 85 18 73.5 Contralateral breast cancer 13 14 8 26.5 0.0228 Other primary cancer (other than contralateral 9 9.5 5 16.5 0.1475 breast cancer) FISH: ﬂuorescence in situ hybridization. Journal of Oncology 5 cancer (3.5–5.5%). Noncarriers had more often G3 tumors. 5.1. All Biological Types of Breast Cancer. +e meta-analysis Contralateral breast cancer developed in 26.5% of BRCA1/2 of 11 studies performed by Lee et al. revealed that patients mutation carriers and in 14% of noncarriers. In both groups, with breast cancer and BRCA1 mutation had worse OS almost half contralateral breast cancers developed before compared to noncarriers (HR � 1.92). +e BRCA2 mutation TNBC diagnosis. Other primary cancers were also slightly did not aﬀect survival in patients with breast cancer more common in BRCA1/2 mutation carriers (16.5% vs (HR � 1.30) [31]. 9.5%). Almost all cases occurred after TNBC diagnosis in In meta-analysis by Zhong et al. [32], based on 13 studies both groups (only 2 cases of lymphoma and one ovarian with 10 016 women with breast cancer, concerning breast cancer developed before TNBC). +e summary of these cancer survival, the BRCA1 mutation carriers had worse OS results is presented in Table 2. than noncarriers (HR � 1.5, p � 0.009) but were not sig- In 72 patients (58% of all TNBC), the primary operation niﬁcantly diﬀerent from noncarriers in terms of progres- was performed. In other 47 (38%) patients, surgery was sion-free survival (HR � 1.35, p � 0.09). carried out after neoadjuvant chemotherapy. Breast-con- In other meta-analysis performed by Zhu et al. [3], based on 34 studies, event-free survival (EFS), OS, and BCSS were serving surgery was more common in BRCA1/2 mutation carriers (41.5% vs 33.5%). Adjuvant chemotherapy was compared in three groups of breast cancer patients: BRCA1 performed in 87 patients (90% after primary surgery). carriers, BRCA2 carriers, and BRCA1/2 noncarriers. In Overall, (neo)adjuvant chemotherapy was performed in a patients with BRCA1 and BRCA2 mutations, OS was worse similar percentage of patients with or without BRCA1/2 than that in patients without mutation (p< 0.001 and mutation. +e summary of patient therapy is presented in p � 0.034, respectively) but did not translate into poor BCSS Table 3. (p � 0.448 and p � 0.401, respectively) or EFS (p � 0.438 We compared RFS, OS, risk of breast cancer death, and and p � 0.558, respectively) [3]. +e BRCA1 mutation was survival from distant metastases in BRCA1/2 carriers and signiﬁcantly associated with worse OS in studies conducted noncarriers. +e performed analysis did not show any in Europe (p< 0.001) and studies assessing patients diag- signiﬁcant diﬀerences between the groups in RFS nosed before 1995 (p< 0.007). +e POSH prospective cohort study analyzed patients (p � 0.312), also after taking into account the clinical stage of TNBC (in patients in the following stages: I: p � 1.0, II: with young-onset breast cancer (≤40 years) regarding the p � 0.454, and III: p � 0.197) or (neo)adjuvant chemo- BRCA1/2 mutation status [33]. Recently published results therapy (p> 0.05). +e risk of the recurrence depending on indicated no signiﬁcant diﬀerence in OS or distant disease- the BRCA1/2 mutation status is shown in Figure 1. +ere was free survival between patients carrying BRCA1/2 mutations no signiﬁcant diﬀerence between patients with or without and patients without those mutations after a diagnosis of BRCA1/2 mutation regarding overall survival (p � 0.649). breast cancer. +e BRCA1/2 mutation was not a prognostic factor of pa- A study by Wang et al. performed on the Chinese cohort tient survival. +e results are presented in Figure 2. +e risk revealed that patients with BRCA1/2 mutations had worse of TNBC death did not diﬀer signiﬁcantly in both groups survival outcomes than noncarriers [25]. BRCA1/2 mutation (Figure 3). carriers were more likely to have lymph node involvement at In 13% (4/30) of BRCA1/2 mutation patients and in 21% initial diagnosis than noncarriers [25]. In our study, we did (20/94) of noncarriers, the recurrence of the disease was not observe these kinds of relations. detected. In both groups, there was one patient with primary metastatic TNBC. +ere was no signiﬁcant diﬀerence in survival from detection of metastases between these two 5.2. Triple-Negative Breast Cancer. Studies that have eval- uated the prognostic role of the BRCA1/2 mutation in pa- groups (p � 0.865). +e results are presented in Figure 4. Among seven variables taken in multivariate analysis, tients with TNBC have shown inconclusive results, but the newest and larger ones are in line with our study. TNM stage was the only factor signiﬁcantly inﬂuencing recurrence and death. +ere was no correlation between RFS In the study performed by Yadav et al. [34], 266 TNBC patients had undergone BRCA1/2 mutation tests. In 27% of or OS and other analyzed risk factors, including the BRCA1/ them, BRCA1/2 mutations were detected. No statistically 2 germline mutation. +e results are shown in Tables 4 and 5. signiﬁcant diﬀerence was found in locoregional recurrence, distant recurrence, RFS, and OS between the breast cancer 5. Discussion patients with and without BRCA1/2 mutations. 5-year OS for BRCA1/2-positive and BRCA1/2-negative breast cancer Our study showed that the outcome of TNBC patients did patients was 83% and 90% and 5-year RFS was 83% and 80%, not diﬀer depending on the BRCA mutation status. We respectively. +e diﬀerences were not statistically signiﬁcant aimed to clarify the prognostic value of BRCA1/2 mutations on breast cancer-speciﬁc outcomes after conventional [34]. In the study by Gonzales-Angulo et al. [22], based on 77 treatment. In our study, RFS, OS, and risk of death from TNBC were similar between patients with breast cancer and TNBC patients, RFS was better for patients with the BRCA1/ 2 mutation and OS was similar between carriers and BRCA1 germline mutation and noncarriers. Because of the noncarriers. fact that among our patients with BRCA1/2 mutations only In another study, Maksimenko et al. [30] compared the one had BRCA2 mutation, the results and discussion con- outcomes of 78 TNBC patients without BRCA1 mutation cern about patients with breast cancer and BRCA1 mutation. 6 Journal of Oncology Table 3: +erapy of 124 TNBC patients assessed for BRCA1/2 mutations. Patients tested for BRCA mutations Type of therapy p value (BRCA-positive vs BRCA-negative) BRCA noncarriers Rate (%) BRCA carriers Rate (%) Number of patients 94 100 30 100 Surgery Yes 90 96 29 97 0.7004 No 4 4 1 3 Type of surgery Mastectomy 60/90 66.5 17/29 58.5 0.2438 Breast-conserving surgery 30/90 33.5 12/29 41.5 Radiotherapy Yes 55 58.5 17 56.5 0.7751 No 39 41.5 13 43.5 Radiotherapy After mastectomy 27/55 49 5/17 29.5 0.0044 After breast-conserving surgery 28/55 51 12/17 70.5 Neoadjuvant chemotherapy Yes 20 21.5 4 13.5 0.0940 No 74 78.5 26 86.5 Regimens in neoadjuvant chemotherapy AT⟶CMF 5/20 25 1/4 25 Anthracycline + taxane 9/20 45 2/4 50 <0.0001 Anthracycline 5/20 5 1/4 25 Others 1/20 25 0 0 Adjuvant chemotherapy Yes 64 68 23 76.5 0.1541 No 30 32 7 23.5 Regimens in adjuvant chemotherapy Anthracycline (AC) 41/64 64 12/23 52 FEC/FAC 11/64 17.5 4/23 17.5 Anthracycline + taxane 8/64 12.5 5/23 21.5 0.0574 CMF 2/64 3 0 0 Taxane 2/64 3 2/23 9 0 20 40 60 80 100 120 140 Time (months) BRCA mutation Negative Positive RFS Median RFS BRCA mutation n p (months) 12 months 24 months 36 months 60 months 120 months Negative 93 96.6% 86.0% 83.6% 77.2% 75.3% Not reached p = 0.312 Positive 29 96.4% 92.9% 85.7% 85.7% 85.7% Not reached Figure 1: Risk of recurrence in TNBC patients depending on the BRCA mutation status. RFS (%) Journal of Oncology 7 0 20 40 60 80 100 120 140 Time (months) BRCA mutation Negative Positive OS Median OS BRCA mutation n p (months) 12 months 24 months 36 months 60 months 120 months Negative 93 97.8% 90.8% 86.1% 78.5% 62.8% Not reached p = 0.649 Positive 29 100% 93.5% 90.3% 86.7% 70.8%Not reached Figure 2: Risk of death in TNBC patients depending on the BRCA mutation status. 0 20406080 100 120 Time (months) BRCA mutation Negative Positive Cumulative probability of death from TNBC Median OS BRCA mutation n p from TNBC 12 months 24 months 36 months 60 months 120 months (months) Negative 93 2.2% 8.0% 11.6% 16.6% 25.3% Not reached p = 0.333 Positive 29 0.0% 6.4% 9.7% 9.7% 13.3% Not reached Figure 3: Relationship between the presence of the BRCA1/2 mutation and the risk of death due to TNBC. OS (%) Cumulative survival from TNBC (%) 8 Journal of Oncology 0 20406080 100 Time (months) BRCA mutation Negative Positive Median survival Survival from metastasis development from metastasis BRCA mutation n p development 12 months 24 months 36 months 60 months (months) Negative 21 52.4% 16.3% 16.3% 10.9% 12.85 p = 0.865 Positive 5 60.0% 40.0% 0.0% 0.0% 12.23 Figure 4: Survival time counted from relapse depending on the BRCA1/2 mutation status. Table 4: Multivariate analysis: ﬁnal model for RFS. estimated. +e authors found that BRCA1 mutation carriers had a 30% higher risk of dying than BRCA1-negative/spo- Factor HR 95% CI p radic cases (OS), but they did not ﬁnd association between Clinical stage: I or II Reference BRCA1 and the risk of death from breast cancer (BCSS). Clinical stage: III 43.26 2.13 880.64 0.014 Contrary to patients with all subtypes of breast cancer, 1748 patients with TNBC and BRCA1/2 mutations had better OS than BRCA1/2-negative ones (HR � 0.49) [24]. +e risk of Table 5: Multivariate analysis: ﬁnal model for OS. recurrence in TNBC was not statistically diﬀerent between BRCA1/2 carriers and BRCA1/2 noncarriers (p � 0.82). Factor HR 95% CI p BCSS and DMFS of BRCA1 mutation carriers did not diﬀer Clinical stage: I Reference from those of BRCA1-negative TNBC patients (p � 0.76 and Clinical stage: II 2.359 1.385 4.016 0.002 p � 0.65, respectively) [24]. Clinical stage: III 8.353 4.918 14.188 <0.001 In the present study, all investigated TNBC cases were diagnosed and treated in one breast cancer department. +e with those of 38 TNBC patients with the BRCA1 mutation. used methods did not diﬀer depending on the BRCA1/2 mutation status, and patients had a long time of follow-up +e BCSS and distant recurrence were signiﬁcantly lower in the BRCA1-positive patients. In 4 other larger studies, there (up to 10 years). Nowadays, new drugs such as poly(- adenosine diphosphate-ribose) polymerase (PARP) inhibi- was no diﬀerence found in recurrence and survival between TNBC carriers and noncarriers of BRCA1/2 mutations tors (olaparib and talazoparib) are dedicated to metastatic BRCA1/2-positive TNBC as well as immunotherapy for [18, 20, 28, 29]. A meta-analysis of 11 papers performed by Xie et al. also revealed that RFS and OS in TNBC patients PDL-1-positive metastatic TNBC [35–37]. +ese drugs can inﬂuence the survival of BRCA1/2 carriers with TNBC in the with and without BRCA1/2 mutations did not diﬀer [20]. Baretta et al. [24] performed a meta-analysis concerning future. In the analyzed cohort with metastatic disease, the the relation between BRCA1/2 mutation and prognosis of survival did not depend on the BRCA1/2 mutation status. In breast cancer based on 105 220 breast cancer patients in- contrast, Larson et al. showed that BRCA carriers with cluding 3588 (3.4%) BRCA1/2 mutation carriers. OS, BCSS, metastatic TNBC had clinically signiﬁcant improved OS at 3 years compared to patients without BRCA mutations (3-year RFS, and distant metastasis-free survival (DMFS) were Survival from metastases (%) Journal of Oncology 9 [3] Y. Zhu, J. Wu, C. Zhang et al., “BRCA mutations and survival OS of 63% vs 28%). In that study also, no patients received in breast cancer: an updated systematic review and meta- treatment with the PARP inhibitor [38]. analysis,” Oncotarget, vol. 7, pp. 70113–70127, 2016. [4] E. Warner, W. Foulkes, P. Goodwin et al., “Prevalence and 6. Limitations of the Study penetrance of BRCA1 and BRCA2 gene mutations in unse- lected Ashkenazi Jewish women with breast cancer,” JNCI +e retrospective nature of the study and a small number of Journal of the National Cancer Institute, vol. 91, no. 14, recurrences or deaths in patients who had undergone genetic pp. 1241–1247, 1999. tests are two main limitations of this study. [5] J. Zhang, R. Pei, Z. Pang et al., “Prevalence and character- Out of 502 consecutive TNBC patients referred to MSCI ization of BRCA1 and BRCA2 germline mutations in Chinese between the years 2005 and 2008, only 124 (25%) patients women with familial breast cancer,” Breast Cancer Research and Treatment, vol. 132, no. 2, pp. 421–428, 2012. underwent genetic tests for the BRCA1/2 mutation. From [6] D. G. Evans, A. Shenton, E. Woodward, F. Lalloo, A. Howell, them, the BRCA1/2 mutation was found only in 30 cases, and E. R. Maher, “Penetrance estimates for BRCA1 and which gives 6% (30/502) BRCA1/2 carriers among 502 BRCA2 based on genetic testing in a clinical cancer genetics TNBC patients. According to the current NCCN guideline service setting: risks of breast/ovarian cancer quoted should and ESMO recommendations, 65% of all TNBC patients reﬂect the cancer burden in the family,” BMC Cancer, vol. 8, from our analysis met the genetic test criteria solely by their no. 1, 2008. age at diagnosis of TNBC (up to 60 years); therefore, the tests [7] D. Ford, D. F. Easton, M. Stratton et al., “Genetic hetero- should be performed [10, 39]. +is number might be even geneity and penetrance analysis of the BRCA1 and BRCA2 higher considering other criteria such as a strong family genes in breast cancer families. +e breast cancer linkage history of breast/ovarian cancer. In the years 2005–2008, consortium,” American Journal of Human Genetics, vol. 62, genetic tests were oﬀered at our institution only for patients no. 62, pp. 676–689, 1998. with a strong family history of breast/ovarian cancer and for [8] D. M. Van der Kolk, G. H. de Bock, B. K. Leegte et al., “Penetrance of breast cancer, ovarian cancer and contralateral those under 45 years at the initial diagnosis of breast cancer. breast cancer in BRCA1 and BRCA2 families: high cancer incidence at older age,” Breast Cancer Research and Treat- 7. Conclusion ment, vol. 124, no. 3, pp. 643–651, 2010. [9] S. Paluch-Shimon, C. Sessa, M. J. Cardoso, F. Gilbert, and Our study demonstrated that the BRCA1 mutation does not E. Senkus, “Prevention and screening in BRCA mutation aﬀect RFS and OS in patients diagnosed with TNBC. +e carriers and other breast/ovarian hereditary cancer syn- outcome of breast cancer in BRCA1 carriers and noncarriers dromes: ESMO Clinical Practice Guidelines for cancer pre- was comparable. +e BRCA1 germline mutation did not vention and screening,” Annals of Oncology, vol. 27, no. suppl inﬂuence the prognosis of the TNBC patients. 5, pp. v103–v110, 2016. 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Effects of BRCA Germline Mutations on Triple-Negative Breast Cancer Prognosis

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Effects of BRCA Germline Mutations on Triple-Negative Breast Cancer Prognosis

Effects of BRCA Germline Mutations on Triple-Negative Breast Cancer Prognosis

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