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Incidence and impact of brain metastasis in patients with hereditary BRCA1 or BRCA2 mutated invasive breast cancer

Incidence and impact of brain metastasis in patients with hereditary BRCA1 or BRCA2 mutated... www.nature.com/npjbcancer ARTICLE OPEN Incidence and impact of brain metastasis in patients with hereditary BRCA1 or BRCA2 mutated invasive breast cancer 1 1 2 3 1 Haven R. Garber , Akshara Singareeka Raghavendra , Michael Lehner , Wei Qiao , Angelica M. Gutierrez-Barrera , 1 1 1 Debu Tripathy , Banu Arun and Nuhad K. Ibrahim Patients with hereditary mutations in BRCA1 or BRCA2 (gBRCA1/2) and breast cancer have distinct tumor biology, and encompass a predilection for brain metastasis (BM). We looked into baseline risk of BMs among gBRCA1/2 patients. Patients with gBRCA1/2, stage I-III invasive breast cancer seen between 2000–2017 with parenchymal BMs. Among gBRCA1 with distant breast cancer recurrence, 34 of 76 (44.7%) were diagnosed with brain metastases compared to 7 of 42 (16.7%) patients with gBRCA2. In the comparator group, 65 of 182 (35.7%) noncarrier triple-negative breast cancer (TNBC) and a distant recurrence experienced BM’s. In a competitive risk analysis using death as a competing factor, the cumulative incidence of BMs was similar between gBRCA1 and noncarrier TNBC patients. The time from primary breast cancer diagnosis to detection of BMs was similar between gBRCA1 and noncarrier TNBC patients (2.4 vs 2.2 years). Survival was poor after BMs (7.8 months for gBRCA1 patients vs. 6.2 months for TNBC noncarriers). Brain was a more common site of initial distant recurrence in gBRCA1 patients versus TNBC noncarriers (26.3% vs. 12.1%). Importantly, the presence of BMs, adversely impacted overall survival across groups (HR 1.68 (95% CI 1.12–2.53), hazard ratio for death if a patient had BMs at the time of initial breast cancer recurrence vs. not). In conclusion, breast cancer BMs is common and is similarly frequent among gBRCA1 and noncarrier patients with recurrent TNBC. Our study highlights the importance of improving the prevention and treatment of BMs in patients with TNBC, gBRCA1 carriers, and noncarriers. npj Breast Cancer (2022) 8:46 ; https://doi.org/10.1038/s41523-022-00407-z INTRODUCTION evaluated talazoparib, ~15% of patients had brain metastases; however, to be eligible, patients with central nervous system (CNS) Hereditary pathogenic variants in the BRCA1 and BRCA2 genes disease had to receive definitive local CNS therapy prior to the substantially increase the risk of developing breast cancer, ovarian study. The investigators reported a comparable benefitof cancer, and other malignancies . Pathogenic variants in either talazoparib in this subgroup of patients compared to the total gene account for ~40% of hereditary breast and ovarian cancers population, though granular data on responses in the CNS were and ~5% of total breast cancers . Both genes function in the repair not provided in the initial report . The combination of veliparib, of double-strand DNA breaks through homologous recombination carboplatin, and paclitaxel also demonstrated superior PFS versus and operate as tumor suppressor genes. Hereditary pathogenic placebo/carboplatin/paclitaxel in the Phase III BROCADE3 trial that variants are typically heterozygous loss-of-function alterations . included 509 patients with gBRCA1/2 and HER2-negative The breast cancer phenotype associated with germline BRCA advanced breast cancer. In BROCADE3, patients with CNS disease pathogenic variants (gBRCA) differs between gBRCA1 and gBRCA2, composed ~5% of those enrolled and so they were not included reflecting their disparate roles in homologous recombination. as a separate subgroup . Breast cancer-associated with gBRCA1 is far more likely to be The prospect of improved systemic disease control with PARP triple-negative breast cancer (TNBC), an aggressive subtype inhibitors and emerging related therapies led us to ask whether associated with a poor prognosis, whereas gBRCA2 breast cancers we might observe more frequent CNS metastases among patients exhibit a similar receptor subtype distribution to sporadic breast with gBRCA in the future, particularly if a propensity for brain cancers . 9–12 metastasis exists in this patient subgroup . This phenomenon Genetic testing for gBRCA is recommended for patients with metastatic breast cancer in whom it could help guide systemic has been observed in patients with metastatic HER2-positive therapy and for patients with any stage breast cancer who are breast cancer as tremendous advances have been made in considered to be at a high risk for hereditary breast cancer . treating systemic disease but effective treatments for CNS Genetic testing results inform breast cancer screening, risk metastasis have lagged. Recently, clinical trials allowing enroll- reduction strategies, and family counseling, and they are now ment of patients with untreated brain metastases have led to the integral to the treatment of metastatic breast cancer. In 2018, the approval of drugs like tucatinib, which demonstrated clear CNS 13–15 FDA approved the Poly (ADP-ribose) polymerase (PARP) inhibitors activity . Data regarding PARP inhibitor penetration of the olaparib and talazoparib for the treatment of HER2-negative, blood-brain barrier (BBB) are mixed and likely relate to the extent gBRCA-associated metastatic breast cancer. Both PARP inhibitors and location of CNS metastases and the associated disruption of 16–18 proved superior to chemotherapy in terms of progression-free the BBB . survival (PFS) in phase III clinical trials that included metastatic The goal of this study was to determine the incidence of brain 6,7 breast cancer patients with gBRCA . In the EMBRACA trial that metastasis in gBRCA patients presenting with early-stage breast 1 2 Department of Breast Medical Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. Departments of UT Internal Medicine Residency Training Program, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. Departments of Biostatistics, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. email: nibrahim@mdanderson.org Published in partnership with the Breast Cancer Research Foundation 1234567890():,; H.R. Garber et al. cancer. We also sought to determine the impact of brain Most patients had a mastectomy for surgical resection of the metastasis on survival in patients with gBRCA and noncarriers primary breast tumor, though approximately 20% or more of with recurrent metastatic breast cancer. A high incidence of brain patients in each group had a partial mastectomy (Table 2). metastasis in gBRCA patients could provide rationale for prioritiz- Systemic chemotherapy was administered for the primary breast ing therapeutic agents with CNS activity, considering brain MRIs at cancer in the majority (>80%) of cases. More than half of patients the time of distant recurrence, and studying the biologic in the gBRCA1 and noncarrier groups received neoadjuvant mechanisms of gBRCA-mediated CNS metastasis. chemotherapy, reflecting the preference for upfront chemother- apy for TNBC. Chemotherapy was largely anthracycline-based across groups. RESULTS For the 106 patients who eventually developed brain metas- Between 2000 and 2017, we identified 473 patients with gBRCA1 tases, the median time to the detection of brain metastases from the initial breast cancer diagnosis was similar between gBRCA1 and 318 patients with gBRCA2 who were evaluated for stage I-III patients and noncarriers (2.4 and 2.2 years) and was longer for breast cancer at MDACC and who were captured in the clinical gBRCA2 patients (5 years), though this was not statistically cancer genetics database. The median length of follow-up for the significant owing to the small size of the gBRCA2 cohort (Table gBRCA1 and gBRCA2 patients was 9.15 years and 8.45 years, 3). Among the 7 gBRCA2 patients who developed eventual brain respectively. A total of 76 of 473 (16.1%) gBRCA1 patients and 42 metastases, all were female, 2 patients had HER2+ disease, and of 318 (13.2%) gBRCA2 patients experienced a distant metastasis the remaining 5 patients had HR+/HER2-negative disease. All 7 from breast cancer (Fig. 1). At 3 years, distant metastasis-free patients received adjuvant chemotherapy for the primary breast survival was inferior in gBRCA1 patients compared to gBRCA2 tumor and 6 of 7 (85.7%) received adjuvant radiation. Due to the patients (86.7%) (95% confidence interval [CI], 83.2–90) vs. 94% small number of gBRCA2 patients with brain metastases, we (95% CI, 90.6–96.1); however, the Kaplan–Meier curves did not focused on estimating the cumulative incidence of brain differ significantly overall (P = 0.25 by log-rank). metastasis among gBRCA1 patients and noncarriers with a distant Brain metastases were diagnosed in 34 of 76 (44.7%) gBRCA1 recurrence. patients with distantly recurrent disease and in 7 of 42 (16.7%) Using death as a competing risk factor, the cumulative gBRCA2 patients with distantly recurrent disease. As expected, the incidence of brain metastasis for gBRCA1 patients at 2 and 5 gBRCA1 patients with distant metastasis had predominantly TNBC years from initial diagnosis was 17.2% (95% CI = 9.7–26.5%) and (77.6%, Table 1) whereas gBRCA2 patients had primarily HR- 38.8% (95% CI = 27.7–49.1%), respectively, compared to 15.4% positive/HER2-negative disease (71.4%). Of the 34 gBRCA1 patients (95% CI = 10.6–21.1%) and 33.3% (95% CI = 26.4–40.3%) for with eventual brain metastasis, 33 had TNBC, and 1 had HR- noncarriers (Fig. 2). In the competitive risk analysis, the cumulative positive/HER2-negative primary breast cancer, though this incidence of brain metastasis was not different between the patient’s disease lost ER/PR expression at the time of distant gBRCA1 and noncarrier cohorts (P = 0.263 by Gray’s test). recurrence. Since the gBRCA1 cohort had the higher incidence of The brain parenchyma was a more frequent site of initial brain metastases and primarily TNBC, gBRCA noncarriers with recurrence in gBRCA1 patients versus noncarriers (20/76 [26.3%] TNBC and distant metastasis were utilized as the comparator vs. 22/182 [12.1%], P = .01 by Fisher’s exact test between the two group. groups). Brain metastases were diagnosed as the initial recurrence Breast cancer was diagnosed at a younger age in gBRCA1 in the absence of extracranial disease (i.e., isolated brain patients compared to gBRCA2 patients and noncarriers (median parenchymal metastases) in 11 of 20 gBRCA1 patients and 9 of age 38 vs. 44.8 vs. 47, P < 0.0001). The median time to genetic 22 noncarriers. Among patients with brain metastasis, approxi- testing was shorter in gBRCA1 patients than in gBRCA2 patients mately one-third of gBRCA1 and noncarrier patients had a solitary brain metastasis whereas 13 of 34 (38.2%) gBRCA1 patients, 6 of 7 and noncarriers (median 3.1 vs. 10.3 vs. 8.1 months, P = 0.029). (85.7%) of gBRCA2 patients, and 32 of 65 (49.2%) noncarriers had Diagnosis of a second primary breast tumor occurred in 5 of 76 more than three brain metastases on the initial brain MRI. The (6.5%) gBRCA1 patients, 5 of 42 (11.9%) of gBRCA2 patients, and 13 treatments administered for brain metastasis included whole- of 182 (7.1%) of noncarriers. Additional patient and disease brain radiotherapy (WBRT), stereotactic radiosurgery or radio- characteristics including patient race, cancer stage, tumor grade, therapy (SRS/SRT), and surgical resection. There were no large and tumor histology are listed in Table 1. differences in the modalities selected for gBRCA1 patients versus noncarriers. The median overall survival (OS) from the time of brain metastasis detection was uniformly poor: 7.8 months in gBRCA1 patients, 26.6 months in gBRCA2 patients, and 6.2 months *ns by log-rank in noncarriers (Fig. 3). The presence of brain metastasis, irrespective of its timing, adversely impacted OS (Fig. 4 and Supplementary Figure 1). For example, the 45 patients who had brain metastases detected at 50 the time of first recurrence had a median OS of 2.5 years gBRCA1 (n=473) compared to 3.4 years for patients who did not have brain gBRCA2 (n=318) metastases at the time of initial recurrence (HR 1.68, 95% CI 1.12–2.53). A similar trend was seen within the gBRCA1 cohort (Supplementary Figure 2). Lastly, we assessed potential clinical predictors of brain 0 5 10 15 20 metastasis among gBRCA1 and noncarrier patients in a multi- Time Since Diagnosis (years) variable logistic regression model. Univariate analyses were Number at risk: performed and variables with P ≤ .1 (breast cancer subtype, gBRCA1 473 300 172 94 53 presence of a second primary breast tumor, tumor grade, adjuvant gBRCA2 318 232 110 58 33 radiation) were then included in a multivariable model (Table 4; Supplementary Tables 1a/1b). In the multivariable model, TNBC Fig. 1 Distant metastasis-free survival. Distant metastasis-free was associated with higher rates of brain metastasis versus other survival for patients diagnosed with stage I-III breast cancer by gBRCA status. breast cancer subtypes, which was expected and biased by our npj Breast Cancer (2022) 46 Published in partnership with the Breast Cancer Research Foundation 1234567890():,; Distant metastasis-free survival H.R. Garber et al. Table 1. Clinical characteristics of patients with distantly recurrent breast cancer by germline BRCA status. BRCA Status germline BRCA1 germline BRCA2 BRCA1/2 non-carrier with P pathogenic variant pathogenic variant TNBC (n = 182) (n = 76) (n = 42) Clinical characteristic Median age at diagnosis (range) 38 (23–72) 44.8 (27–76) 47 (19–79) <0.0001 Median time from diagnosis to hereditary genetic 3.1 (0.8–16) 10.3 (1.2–114.1) 8.1 (1.8–28.1) 0.029 testing (IQR) in months No. of Patients % No. of Patients % No. of Patients % Sex Female 76 100 39 92.9 182 100 Male 3 7.1 Race White 41 53.9 32 76.2 118 64.8 <0.0001 Black 15 19.7 3 7.1 31 17.0 Hispanic 13 17.1 3 7.1 24 13.2 Asian/Pacific Islander 5 6.6 4 9.5 6 3.3 Other 2 2.6 3 1.6 Breast cancer subtype* TNBC 59 77.6 4 9.5 178 97.8 <0.0001 HR-positive/HER2-negative 8 10.5 30 71.4 HER2-positive 3 3.9 5 11.9 HR-positive/HER2 unknown 2 2.6 3 7.1 HR-negative/HER2 unknown 2 2.6 4 2.2 Unknown 2 2.6 2nd primary breast cancer 5 6.6 5 11.9 13 7.1 0.532 Stage (anatomic) 1 16 21.1 11 26.2 18 9.9 0.027 2 29 38.2 18 42.9 91 50.0 3 29 38.2 13 31.0 73 40.1 Unknown 2 2.6 Tumor grade 1 3 3.9 2 1.1 <0.0001 2 12 15.8 20 47.6 18 9.9 3 56 73.7 20 47.6 157 86.3 Unknown 5 6.6 2 4.8 5 2.7 Histology IDC 71 93.4 36 85.7 163 89.6 <0.0001 ILC 1 1.3 5 (mixed IDC/ILC) 11.9 4 (3 are mixed IDC/ 2.2 ILC) Other or breast cancer, NOS 3 3.9 1 2.4 15 8.2 Unknown 1 1.3 *For patients with a second primary breast cancer, the most recent subtype is listed. inclusion of noncarriers with TNBC only. Importantly, the model and gBRCA1. There was no difference in predilection to extra produced similar results with the breast cancer subtype variable cranial metastasis between gBRCA1 or gBRCA2 but revealed less incidence and longer time to brain metastasis of the tumors that removed (Supplemental Table 2). In addition, the odds ratio for brain metastasis among patients having received prior adjuvant are gBRCA2 mutated compared to those that are gBRCA1 mutated or non BRCA mutated TN breast cancer tumors. Among gBRCA1 radiation for a primary breast cancer versus no adjuvant radiation was 2.3 (95% CI 1.26–4.19, P = .0066). patients diagnosed with stage I-III breast cancer, 76 of 473 (16%) patients experienced a distant recurrence, and 34 of these 76 (44.7%) patients were diagnosed with brain metastases. The DISCUSSION frequency of brain metastasis among gBRCA2 patients with a Our study of breast cancer patients with hereditary pathogenic distant recurrence was lower, with brain metastases detected in 7 variants in gBRCA1 or gBRCA2 revealed a high frequency of brain of 42 (16.7%) gBRCA2 patients in our cohort. As a comparator metastasis among women with distantly recurrent breast cancer group for the gBRCA1 cohort, we utilized patients diagnosed with Published in partnership with the Breast Cancer Research Foundation npj Breast Cancer (2022) 46 H.R. Garber et al. Table 2. Treatment characteristics of patients with distantly recurrent breast cancer by germline BRCA status. BRCA Status germline BRCA1 germline BRCA2 BRCA1/2 noncarrier with P pathogenic variant pathogenic variant TNBC (n = 182) (n = 76) (n = 42) No. of Patients % No. of Patients % No. of Patients % Treatment characteristic* Surgery type Partial mastectomy 16 21 8 19 66 36 0.04 Mastectomy 57 75 34 81 112 62 ALND only for occult breast primary 0 0 0 0 2 1 Unknown 3 4 0 0 2 1 Chemotherapy Neoadjuvant 40 53 15 36 97 53 0.0001 Adjuvant 13 17 16 38 66 36 No chemotherapy 14 18 7 17 5 3 Neoadjuvant + adjuvant 9 12 4 10 14 8 Chemotherapy regimen Anthracycline-based (non-taxane) 12 17 8 21 27 14 Anthracycline + taxane 46 65 23 59 135 71 Taxane based 8 11 6 15 23 12 else 5 7 2 5 6 3 Radiation therapy Yes 47 62 30 71 126 69 0.677 No 26 34 12 29 56 31 Unknown 3 4 0 0 0 0 *For patients with a second primary breast cancer, the treatment for the most recent breast cancer is listed. These patients primarily received FAC chemotherapy. stage I-III TNBC with recurrent breast cancer who had tested considered as an initial event or at any time during the disease course. negative for variants in BRCA1 and BRCA2. In a competitive risk We were interested in the baseline risk of brain metastasis analysis using death as a competing risk factor, the cumulative among gBRCA1 and gBRCA2 patients in the pre-PARP inhibitor era incidence of brain metastasis did not differ between gBRCA1 to serve as context for evaluating CNS recurrences and responses patients and TNBC noncarrier patients. In addition, the time from now that PARP inhibitors and PARP inhibitors combinations are primary breast cancer diagnosis to the detection of brain increasingly utilized in the adjuvant and metastatic settings . metastasis was similar between gBRCA1 patients and TNBC PARP inhibitors improve systemic disease control and progression- noncarriers (2.4 vs. 2.2 years). One difference was that the brain free survival (an OS benefit has not been shown) versus standard was a more common site of initial distant recurrence in gBRCA1 chemotherapy, including in patients with treated brain metas- patients versus TNBC noncarriers (26.3% vs. 12.1%). In a multi- tases; however, their overall efficacy in the CNS remains uncertain. variable logistic regression model, aside from TNBC subtype, only Two other institutions have reported their experience with gBRCA the receipt of prior adjuvant radiation (vs. no prior adjuvant breast cancer patients and CNS recurrence. The Dana Farber radiation) for primary breast cancer treatment was associated with Cancer Institute (DFCI)/Beth Israel Deaconess Medical Center the eventual development of brain metastasis. We postulate that (BIDMC) gBRCA cohort has been the focus of several important this is likely related to more aggressive primary tumors, those with 10,11,20 reports . Lee et al. studied 46 gBRCA1 and 71 BRCA noncarrier a greater propensity to recur, being dispositioned to adjuvant early-stage breast cancer patients who had received alkylating radiation rather than due to untoward direct genotoxic effects chemotherapy and found that the rate and distribution of distant from the radiation itself on residual tumor cells. Our multivariable 20 metastasis and OS was similar between the two groups . They model did not consider variables such as tumor stage/nodal stage reported a potential propensity for brain metastasis among (we included overall anatomic stage), proliferation index (Ki-67), gBRCA1 patients (7 of 12 [58%] gBRCA1 patients with brain margin status, and lymphovascular invasion, which may explain metastasis vs. 5 of 21 (24%) noncarriers), which they examined in why the adjuvant radiation variable was significantly associated further detail in a follow-up report. This study included additional with brain metastasis in our model. patients (a total of 89 gBRCA1 and 175 noncarriers) and again Patient survival after the detection of brain metastasis was compared the clinical outcomes of early-stage breast cancer expectedly poor across subgroups and was only 7.8 months for patients treated with chemotherapy based on gBRCA1 status, gBRCA1 patients and 6.2 months in TNBC noncarriers. Survival limiting the analyses to the TNBC subtype. No difference was after brain metastasis was longer in gBRCA2 patients (2.2 years), observed between the two groups in terms of recurrence site, though interpretation of these data is limited by the small cohort freedom from distant metastasis, or breast cancer-specific survival. size (n = 7 patients). Brain metastasis had an adverse impact on The frequency of brain metastasis in gBRCA1 patients with a survival in comparison to other sites of distant metastasis when distant breast cancer recurrence in this study was 7 of 19 (36.8%) npj Breast Cancer (2022) 46 Published in partnership with the Breast Cancer Research Foundation H.R. Garber et al. Table 3. Characteristics of brain metastases in patients with distantly recurrent breast cancer by germline BRCA status. BRCA Status germline BRCA1 germline BRCA2 BRCA1/2 noncarrier P pathogenic variant pathogenic variant with TNBC (n = 76) (n = 42) (n = 182) No. of %No.of %No.of % Patients Patients Patients Breast cancer brain metastases detected at any time during patient’s course Yes 34 44.7 7 16.7 65 35.7 0.009 No 42 55.3 35 83.3 117 64.3 Median time to detection of brain metastases (years from date of 2.4 (0.7–31.9) 4.98 (1.7–14.4) 2.2 (0.5–6.5) 0.12 diagnosis, range) Was the brain a site of initial distant recurrence? Yes 20 26.3 3 7.1 22 12.1 0.058 No, brain mets were found later in course 14 18.4 4 9.5 43 23.6 No brain mets 42 55.3 35 83.3 117 64.3 If brain mets were among the initial site(s) of distant recurrence, was 0.53 extracranial disease absent or present at the time of recurrence? Extracranial disease absent 11 1 9 0.587 Extracranial disease present 9 2 13 Number of brain metastases at time of initial detection (as a %age of patients w/brain metastasis) solitary 12 35.3 1 14.3 21 32.3 0.2501 2–3 brain metastases 8 23.5 11 16.9 >3 brain metastases 13 38.2 6 85.7 32 49.2 unknown 1 2.9 1 1.5 Treatment for initial brain metastases* WBRT 22 56.4 4 50 36 48.6 SRS/SRT 8 20.5 25 33.8 Resection 8 20.5 2 25 10 13.5 Hospice 1 2.6 2 25 3 4.1 Unknown *Many patients were treated with multimodality therapy (e.g., resection followed by either SRS or WBRT). All treatments administered for the patients’ initial presentation of brain metastases are listed. BRCA1 Neg gBRCA1 (n=34) gBRCA2 (n=7) non-carriers (n=65) *ns by log-rank Gray's test P−value=0.263 0.0 2.5 5.0 Time Since Detection of Brain Metastasis (years) 0 5 10 15 20 25 30 35 Number at risk: gBRCA1 34 7 3 Time from diagnosis (years) gBRCA2 7 3 2 Fig. 2 Cumulative incidence of brain metastasis. Estimates of the non-carrier 65 8 2 cumulative incidence of brain metastasis are shown for gBRCA1 Fig. 3 Overall Survival with brain metastasis. Overall survival from patients (n = 76) and noncarriers with triple negative breast cancer the time of brain metastasis detection for breast cancer patients by (n = 182) diagnosed with stage I-III disease with subsequent distant gBRCA status. recurrence. Published in partnership with the Breast Cancer Research Foundation npj Breast Cancer (2022) 46 cumulative incidene for brain metastasis 0.0 0.2 0.4 0.6 0.8 1.0 Percent survival H.R. Garber et al. brain metastases are a site of initial gBRCA2 as a risk factor for brain metastasis compared to distant recurrence, n=45 100 noncarriers, our comparator group included only patients with brain metastases are not among the TNBC, whereas gBRCA2 breast cancer is predominantly HR+, and site(s) of initial distant recurrence,n=255 so our data do not address that specific question. A smaller study from Gustave Roussy reported parenchymal *P=.0018 by log-rank brain metastasis among patients with distantly recurrent breast cancer in 10/15 (66.7%) gBRCA1 patients, 0/12 gBRCA2 patients, and 6/58 (10.3%) noncarriers (all breast tumor subtypes included) . Taken together, these reports from the DFCI/BIDMC and Gustave Roussy along with our data from MDACC confirm a high rate of brain metastasis among gBRCA1 patients and 05 10 noncarriers with TNBC. There is no clear signal from the clinical Time Since Diagnosis (years) Number at risk: data that gBRCA breast cancers have a unique predilection for the brain met at CNS, especially when compared to patients with TNBC, though it is initial recurrence 45 12 1 plausible that different biologic mechanisms account for the high no brain met at initial recurrence 255 90 41 rate of CNS invasion in gBRCA1 versus noncarrier TNBC recurrences. Investigators have studied brain metastasis in other Fig. 4 Overall Survival with distant recurrence. Overall survival BRCA-associated malignancies. Data from small cohorts suggest from the time of diagnosis for patients with recurrent breast cancer that gBRCA ovarian cancer patients may be at a higher risk for stratified by the presence or absence of brain metastases among the initial sites of disease recurrence. brain metastasis (or isolated brain metastasis), though the overall rate (~2.5%) is far lower than seen in breast cancer. Alternatively, those data may be explained by longer overall survival in gBRCA ovarian cancer patients attributable to enhanced chemosensitivity Table 4. Multivariable logistic regression of potential clinical factors in 21–26 and effective PARP inhibitor maintenance therapy . Brain brain metastasis (n = 258 gBRCA1 and non-carrier patients). metastasis in gBRCA pancreatic cancer patients is case reportable 27–29 Effect Odds Ratio 95% Wald and is similarly rare in metastatic prostate cancer . Estimates Interestingly, increased homologous recombination deficiency Confidence Limits p- (in wild-type BRCA1/2 tumors) has been observed among breast value 30,31 cancer brain metastases . In one study that examined the Tumor grade (III vs. I/II) 2.425 0.971 6.055 0.0579 molecular features of paired primary breast tumors/brain metas- tases, an increase in homologous recombination deficiency was Breast ca subtype (others 0.082 0.01 0.636 0.0167 observed in the brain metastasis compared to the primary tumor vs TNBC) in 14/16 (87.5%) of the cases . Similar data have been reported Presence of a second 0.25 0.053 1.186 0.081 for colorectal cancer brain metastases . The investigators primary tumor hypothesize that higher levels of homologous recombination Adj radiation (Yes vs. no) 2.296 1.261 4.181 0.0066 deficiency may enable tumor cells to adapt more readily to the CNS microenvironment. In a systematic review of the genetic landscape of breast cancer brain metastases, several genes involved in DNA damage repair were among the 22 most patients and was 11 of 40 (27.5%) for noncarriers . Our analysis of frequently altered genes in brain metastases, including BRCA1, the MDACC cohort generally agrees with these data in demon- BRCA2, MLH1, ATR, ATM, and CHEK2 whereas these genes were not strating that the cumulative incidence of brain metastasis among among the most altered genes cataloged in extracranial distant gBRCA1 and TNBC patients is similarly high. When we modified the 33–35 recurrences . Accordingly, two genes integral to homologous competitive risk analysis to include only gBRCA1 patients who had recombination, BARD1, and RAD51, were found to be over- TNBC primary tumors (rather than other subtypes), the cumulative expressed in breast cancer brain metastases compared to incidence of brain metastasis was significantly higher among matched primary breast tumors, and when overexpressed in a gBRCA1 TNBC patients vs. noncarrier TNBC patients (Supplemen- human breast cancer cell line, these genes mediated increased tary Figure 3). brain metastases in mouse xenograft models . No studies have In a recent analysis of the DFCI gBRCA cohort, the authors focused exclusively on the molecular features of gBRCA brain reported a frequency of CNS metastasis (including parenchymal metastases, and it would be interesting to determine whether and leptomeningeal disease) among patients with recurrent these tumors undergo less genomic evolution upon CNS invasion breast cancer of 16/30 (53%) in gBRCA1 patients, 16/32 (50%) in since homologous recombination deficiency is intrinsic to the gBRCA2 patients, and 67/270 (25%) in noncarriers (including all primary tumor. In addition, if TNBC tumors do become more breast tumor subtypes, >50% HR+/HER2-negative) . In a multi- BRCA-like upon seeding the brain, there is the possibility for variable model within their study, only gBRCA2 was significantly therapeutic activity of PARP inhibitors with adequate CNS associated with CNS metastasis. The frequency of reported CNS penetration. For example, it will be important to assess whether metastasis in their gBRCA2 cohort was higher than in ours [16/32 olaparib, as evaluated in the phase III OlympiA trial, was effective 19,37 (50%) vs. 7/42 (16.7%)]. Both DFCI and MDACC are subject to at preventing both systemic and CNS recurrences . referral bias though differences in the timing of referral may be Our study has several limitations. First, gBRCA patients with one factor that explains the discrepancy. A second factor is that early-stage breast cancer have a good prognosis and, fortunately, 38,39 our primary event of interest was parenchymal brain metastasis distant metastasis is infrequent . Of the 791 gBRCA early stage rather than combined parenchymal brain metastasis/leptomenin- breast cancer patients that were followed longitudinally at geal disease. A third difference is that Song et al. relied on two MDACC, ~15% developed a distant recurrence, and the overall databases, one that included only patients with recurrent breast frequency of brain metastasis in the total gBRCA cohort was ~5%. cancer whereas we utilized one prospectively maintained As a result, our single-institution cohort of gBRCA patients with database that included all patients referred for genetic testing. distantly recurrent breast cancer is small, though it is larger/ Lastly, the gBRCA2 cohorts were limited in size in both studies. comparable to those from previous reports. Second, the true With regard to the multivariable model in Song et al. that showed incidence of brain metastasis is unknown since routine brain MRI npj Breast Cancer (2022) 46 Published in partnership with the Breast Cancer Research Foundation Percent survival H.R. Garber et al. screening is not recommended and is typically reserved for surgery for primary breast cancer, chemotherapy delivered for primary breast cancer, distant recurrence and date if applicable, location of distant symptomatic patients. Thus, the estimates we provide almost recurrence, and brain metastasis and date of detection if applicable. Brain certainly underestimate the true incidence. Third, though the metastasis characteristics and the treatment administered for the initial brain clinical genetics database at MDACC is prospectively maintained metastases were also abstracted from patients’ charts. Patients with Stage IV and routinely updated, our study is retrospective in its scope and de novo metastatic disease were excluded. there are many uncontrolled factors including date of gBRCA Tumors were considered triple negative if both ER and PR were negative testing, receipt and type of chemotherapy, and length of follow- (<10% tumor staining) and HER2 was considered non-amplified. up. A minor fraction of patients in all groups were lost to follow- HER2 status was assessed by immunohistochemistry or fluorescence up. Nonetheless, the strengths of our study include its use of a in situ hybridization when indicated and considered positive or negative single, large database with comprehensive clinical annotation and on the basis of institutional cutoffs and guidelines that were current at the time of diagnosis. For tumor grade, composite histologic grade was used the manual verification of all clinical data reported. The MDACC when available and if unavailable, nuclear grade was used. For patients genetics clinic is an active and longitudinal program, reflected by with a second primary breast cancer, the most recent primary breast the ~9-year median length of follow-up for gBRCA patients. As a cancer was used in the analysis. result, we believe the data provided in this report are representative of the larger gBRCA population. Statistical analyses In conclusion, brain metastasis is a similarly frequent event Continuous variables are reported as mean or median (and range or among gBRCA1 patients and gBRCA noncarriers with recurrent interquartile range [IQR]). The distribution of each categorical variable is TNBC. In a competitive risk analysis from the time of primary summarized in terms of its frequency and percentage. Distant metastasis- breast cancer diagnosis, the 5-yr cumulative incidence of brain free survival was defined as the time from primary breast cancer diagnosis metastasis among patients with recurrent breast cancer was 38.8% to distant metastasis (bone, liver, lung, CNS parenchyma, non-regional for gBRCA1 patients and 33.3% for noncarriers with TNBC (P = lymph node, etc.) or death from any cause. Patients still alive at the time of 0.26). Interestingly, studies of the molecular features of paired analysis were censored at their last date of follow-up. Time to brain primary breast cancer/brain metastasis specimens, most of which metastasis was computed from the date of diagnosis of the primary breast are BRCA1/2 wild-type, suggest that breast cancer cells capable of cancer to the date of detection of brain metastasis on imaging or last CNS propagation have increased homologous recombination follow-up. The cumulative incidence of brain metastases was estimated by deficiency, a characteristic intrinsic to BRCA1/2-deficient tumors. Fine-Gray competing risk approach, considering death as a competing risk . Among patients who developed brain metastasis, survival following The therapeutic efficacy of PARP inhibitors for the treatment or brain metastasis was computed from the date of detection of brain prevention of CNS recurrence in BRCA-mutant (hereditary or metastasis to the date of death or last follow-up. Categorical data were somatic) or BRCA wild-type breast cancer is largely unknown, compared using the Χ or Fisher’s exact test. Continuous data were though the currently approved PARP inhibitors are unlikely to compared using Wilcoxon rank sum test (two groups) or Kruskal–Wallis test mediate durable CNS responses as monotherapy. Our study aligns (three groups). All tests were two-sided and P values < 0.05 were with prior reports and underscores the importance of improving considered statistically significant as exploratory analyses. We used the the prevention and treatment of brain metastasis in patients with Kaplan–Meier method to estimate survival and compared survival curves recurrent TNBC, both in gBRCA1 carriers and noncarriers. using the log-rank test. Computations were carried out using SAS version 9.4 and R 4.0.2 and GraphPad Prism 8. METHODS Reporting summary Patient population and data collection Further information on research design is available in the Nature Research Approval was obtained from the institutional review board at UT MD Reporting Summary linked to this article. Anderson Cancer Center (MDACC, approval no. PA18-0386). A waiver of consent was obtained to ensure ethical standards of data use due to the retrospective nature of the study. To determine the incidence of brain DATA AVAILABILITY metastasis among gBRCA patients and gBRCA noncarriers, we queried an The data that support the findings of this study are available from the corresponding IRB-approved, prospectively maintained electronic database that includes author, upon reasonable request. patients referred to the MDACC clinical cancer genetics program who underwent gBRCA testing. Patients who test positive for various germline Received: 29 September 2021; Accepted: 24 February 2022; mutations or negative (noncarriers) are included in the database. We identified patients within the database with stage I-III invasive breast cancer who were evaluated at MDACC between 2000-2017 and who tested positive for hereditary mutations in BRCA1 or BRCA2 and assessed for disease recurrence and parenchymal brain metastasis. Patients with variants of uncertain significance in gBRCA were excluded from the REFERENCES analysis. 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Efficacy of Carboplatin alone and in combination with ABT888 in intracranial murine models of BRCA-mutated and BRCA-wild-type triple- negative breast cancer. Mol. Cancer Ther. 14, 920–30 (2015). AUTHOR CONTRIBUTIONS 19. Tutt, A. N. J. et al. Adjuvant Olaparib for patients with BRCA1- or BRCA2-mutated Design/conception: B.A., H.R.G., N.K.I., Data collection: A.S.R., M.L., A.M.G., Statistical. breast cancer. N. Engl. J. Med. 384, 2394–2405 (2021). analysis: H.R.G., W.Q., Data interpretation: all authors. Manuscript writing: all authors. 20. Lee, L. J. et al. Clinical outcome of triple negative breast cancer in BRCA1 mutation carriers and noncarriers. Cancer 117, 3093–3100 (2011). 21. Borella, F. et al. Brain metastases from ovarian cancer: current evidence in COMPETING INTERESTS diagnosis, treatment, and prognosis. Cancers 12, 2156 (2020). 22. Gourley, C. et al. Increased incidence of visceral metastases in scottish patients The authors declare no competing interests. with BRCA1/2-defective ovarian cancer: an extension of the ovarian BRCAness phenotype. J. Clin. Oncol. 28, 2505–2511 (2010). 23. Sekine, M. et al. Increased incidence of brain metastases in BRCA1-related ovarian ADDITIONAL INFORMATION cancers. J. Obstet. Gynaecol. Res. 39, 292–296 (2013). Supplementary information The online version contains supplementary material 24. Stasenko, M. et al. Brain metastasis in epithelial ovarian cancer by BRCA1/2 available at https://doi.org/10.1038/s41523-022-00407-z. mutation status. Gynecol. Oncol. 154, 144–149 (2019). 25. Ratner, E. et al. Increased risk of brain metastases in ovarian cancer patients with Correspondence and requests for materials should be addressed to Nuhad K. BRCA mutations. Gynecol. Oncol. 153, 568–573 (2019). Ibrahim. 26. Balendran, S. et al. Next-generation sequencing-based genomic profiling of brain metastases of primary ovarian cancer identifies high number of BRCA-mutations. Reprints and permission information is available at http://www.nature.com/ J. Neurooncol. 133, 469–476 (2017). reprints 27. Sonnenblick, A. et al. Defects in homologous recombination repair genes are associated with good prognosis and clinical sensitivity to DNA-damaging agents Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in pancreatic cancer: A case report. Mol. Clin. Oncol. 8, 683–685 (2018). in published maps and institutional affiliations. 28. Jordan, E. J. et al. Brain metastases in pancreatic ductal adenocarcinoma: assessment of molecular genotype-phenotype features-an entity with an increasing incidence?. Clin. Colorectal Cancer 17, e315–e321 (2018). 29. Patel, M. et al. Clinical, genetic, and pathologic determinants of prostate cancer Open Access This article is licensed under a Creative Commons brain metastasis. J. Clin. Oncol. 38, 5536–5536 (2020). Attribution 4.0 International License, which permits use, sharing, 30. Diossy, M. et al. Breast cancer brain metastases show increased levels of genomic adaptation, distribution and reproduction in any medium or format, as long as you give aberration-based homologous recombination deficiency scores relative to their appropriate credit to the original author(s) and the source, provide a link to the Creative corresponding primary tumors. Ann. Oncol. 29, 1948–1954 (2018). Commons license, and indicate if changes were made. The images or other third party 31. Tyran, M. et al. A comparison of DNA mutation and copy number profiles of material in this article are included in the article’s Creative Commons license, unless primary breast cancers and paired brain metastases for identifying clinically indicated otherwise in a credit line to the material. If material is not included in the relevant genetic alterations in brain metastases. Cancers 11, 5 (2019). article’s Creative Commons license and your intended use is not permitted by statutory 32. Sun, J. et al. Genomic signatures reveal DNA damage response deficiency in regulation or exceeds the permitted use, you will need to obtain permission directly colorectal cancer brain metastases. Nat. Commun. 10, 3190 (2019). from the copyright holder. To view a copy of this license, visit http://creativecommons. 33. Morgan, A. J., Giannoudis, A. & Palmieri, C. The genomic landscape of breast org/licenses/by/4.0/. cancer brain metastases: a systematic review. Lancet Oncol. 22,e7–e17 (2021). 34. Bertucci, F. et al. Genomic characterization of metastatic breast cancers. Nature 569, 560–564 (2019). © The Author(s) 2022 npj Breast Cancer (2022) 46 Published in partnership with the Breast Cancer Research Foundation http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png npj Breast Cancer Springer Journals

Incidence and impact of brain metastasis in patients with hereditary BRCA1 or BRCA2 mutated invasive breast cancer

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www.nature.com/npjbcancer ARTICLE OPEN Incidence and impact of brain metastasis in patients with hereditary BRCA1 or BRCA2 mutated invasive breast cancer 1 1 2 3 1 Haven R. Garber , Akshara Singareeka Raghavendra , Michael Lehner , Wei Qiao , Angelica M. Gutierrez-Barrera , 1 1 1 Debu Tripathy , Banu Arun and Nuhad K. Ibrahim Patients with hereditary mutations in BRCA1 or BRCA2 (gBRCA1/2) and breast cancer have distinct tumor biology, and encompass a predilection for brain metastasis (BM). We looked into baseline risk of BMs among gBRCA1/2 patients. Patients with gBRCA1/2, stage I-III invasive breast cancer seen between 2000–2017 with parenchymal BMs. Among gBRCA1 with distant breast cancer recurrence, 34 of 76 (44.7%) were diagnosed with brain metastases compared to 7 of 42 (16.7%) patients with gBRCA2. In the comparator group, 65 of 182 (35.7%) noncarrier triple-negative breast cancer (TNBC) and a distant recurrence experienced BM’s. In a competitive risk analysis using death as a competing factor, the cumulative incidence of BMs was similar between gBRCA1 and noncarrier TNBC patients. The time from primary breast cancer diagnosis to detection of BMs was similar between gBRCA1 and noncarrier TNBC patients (2.4 vs 2.2 years). Survival was poor after BMs (7.8 months for gBRCA1 patients vs. 6.2 months for TNBC noncarriers). Brain was a more common site of initial distant recurrence in gBRCA1 patients versus TNBC noncarriers (26.3% vs. 12.1%). Importantly, the presence of BMs, adversely impacted overall survival across groups (HR 1.68 (95% CI 1.12–2.53), hazard ratio for death if a patient had BMs at the time of initial breast cancer recurrence vs. not). In conclusion, breast cancer BMs is common and is similarly frequent among gBRCA1 and noncarrier patients with recurrent TNBC. Our study highlights the importance of improving the prevention and treatment of BMs in patients with TNBC, gBRCA1 carriers, and noncarriers. npj Breast Cancer (2022) 8:46 ; https://doi.org/10.1038/s41523-022-00407-z INTRODUCTION evaluated talazoparib, ~15% of patients had brain metastases; however, to be eligible, patients with central nervous system (CNS) Hereditary pathogenic variants in the BRCA1 and BRCA2 genes disease had to receive definitive local CNS therapy prior to the substantially increase the risk of developing breast cancer, ovarian study. The investigators reported a comparable benefitof cancer, and other malignancies . Pathogenic variants in either talazoparib in this subgroup of patients compared to the total gene account for ~40% of hereditary breast and ovarian cancers population, though granular data on responses in the CNS were and ~5% of total breast cancers . Both genes function in the repair not provided in the initial report . The combination of veliparib, of double-strand DNA breaks through homologous recombination carboplatin, and paclitaxel also demonstrated superior PFS versus and operate as tumor suppressor genes. Hereditary pathogenic placebo/carboplatin/paclitaxel in the Phase III BROCADE3 trial that variants are typically heterozygous loss-of-function alterations . included 509 patients with gBRCA1/2 and HER2-negative The breast cancer phenotype associated with germline BRCA advanced breast cancer. In BROCADE3, patients with CNS disease pathogenic variants (gBRCA) differs between gBRCA1 and gBRCA2, composed ~5% of those enrolled and so they were not included reflecting their disparate roles in homologous recombination. as a separate subgroup . Breast cancer-associated with gBRCA1 is far more likely to be The prospect of improved systemic disease control with PARP triple-negative breast cancer (TNBC), an aggressive subtype inhibitors and emerging related therapies led us to ask whether associated with a poor prognosis, whereas gBRCA2 breast cancers we might observe more frequent CNS metastases among patients exhibit a similar receptor subtype distribution to sporadic breast with gBRCA in the future, particularly if a propensity for brain cancers . 9–12 metastasis exists in this patient subgroup . This phenomenon Genetic testing for gBRCA is recommended for patients with metastatic breast cancer in whom it could help guide systemic has been observed in patients with metastatic HER2-positive therapy and for patients with any stage breast cancer who are breast cancer as tremendous advances have been made in considered to be at a high risk for hereditary breast cancer . treating systemic disease but effective treatments for CNS Genetic testing results inform breast cancer screening, risk metastasis have lagged. Recently, clinical trials allowing enroll- reduction strategies, and family counseling, and they are now ment of patients with untreated brain metastases have led to the integral to the treatment of metastatic breast cancer. In 2018, the approval of drugs like tucatinib, which demonstrated clear CNS 13–15 FDA approved the Poly (ADP-ribose) polymerase (PARP) inhibitors activity . Data regarding PARP inhibitor penetration of the olaparib and talazoparib for the treatment of HER2-negative, blood-brain barrier (BBB) are mixed and likely relate to the extent gBRCA-associated metastatic breast cancer. Both PARP inhibitors and location of CNS metastases and the associated disruption of 16–18 proved superior to chemotherapy in terms of progression-free the BBB . survival (PFS) in phase III clinical trials that included metastatic The goal of this study was to determine the incidence of brain 6,7 breast cancer patients with gBRCA . In the EMBRACA trial that metastasis in gBRCA patients presenting with early-stage breast 1 2 Department of Breast Medical Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. Departments of UT Internal Medicine Residency Training Program, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. Departments of Biostatistics, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. email: nibrahim@mdanderson.org Published in partnership with the Breast Cancer Research Foundation 1234567890():,; H.R. Garber et al. cancer. We also sought to determine the impact of brain Most patients had a mastectomy for surgical resection of the metastasis on survival in patients with gBRCA and noncarriers primary breast tumor, though approximately 20% or more of with recurrent metastatic breast cancer. A high incidence of brain patients in each group had a partial mastectomy (Table 2). metastasis in gBRCA patients could provide rationale for prioritiz- Systemic chemotherapy was administered for the primary breast ing therapeutic agents with CNS activity, considering brain MRIs at cancer in the majority (>80%) of cases. More than half of patients the time of distant recurrence, and studying the biologic in the gBRCA1 and noncarrier groups received neoadjuvant mechanisms of gBRCA-mediated CNS metastasis. chemotherapy, reflecting the preference for upfront chemother- apy for TNBC. Chemotherapy was largely anthracycline-based across groups. RESULTS For the 106 patients who eventually developed brain metas- Between 2000 and 2017, we identified 473 patients with gBRCA1 tases, the median time to the detection of brain metastases from the initial breast cancer diagnosis was similar between gBRCA1 and 318 patients with gBRCA2 who were evaluated for stage I-III patients and noncarriers (2.4 and 2.2 years) and was longer for breast cancer at MDACC and who were captured in the clinical gBRCA2 patients (5 years), though this was not statistically cancer genetics database. The median length of follow-up for the significant owing to the small size of the gBRCA2 cohort (Table gBRCA1 and gBRCA2 patients was 9.15 years and 8.45 years, 3). Among the 7 gBRCA2 patients who developed eventual brain respectively. A total of 76 of 473 (16.1%) gBRCA1 patients and 42 metastases, all were female, 2 patients had HER2+ disease, and of 318 (13.2%) gBRCA2 patients experienced a distant metastasis the remaining 5 patients had HR+/HER2-negative disease. All 7 from breast cancer (Fig. 1). At 3 years, distant metastasis-free patients received adjuvant chemotherapy for the primary breast survival was inferior in gBRCA1 patients compared to gBRCA2 tumor and 6 of 7 (85.7%) received adjuvant radiation. Due to the patients (86.7%) (95% confidence interval [CI], 83.2–90) vs. 94% small number of gBRCA2 patients with brain metastases, we (95% CI, 90.6–96.1); however, the Kaplan–Meier curves did not focused on estimating the cumulative incidence of brain differ significantly overall (P = 0.25 by log-rank). metastasis among gBRCA1 patients and noncarriers with a distant Brain metastases were diagnosed in 34 of 76 (44.7%) gBRCA1 recurrence. patients with distantly recurrent disease and in 7 of 42 (16.7%) Using death as a competing risk factor, the cumulative gBRCA2 patients with distantly recurrent disease. As expected, the incidence of brain metastasis for gBRCA1 patients at 2 and 5 gBRCA1 patients with distant metastasis had predominantly TNBC years from initial diagnosis was 17.2% (95% CI = 9.7–26.5%) and (77.6%, Table 1) whereas gBRCA2 patients had primarily HR- 38.8% (95% CI = 27.7–49.1%), respectively, compared to 15.4% positive/HER2-negative disease (71.4%). Of the 34 gBRCA1 patients (95% CI = 10.6–21.1%) and 33.3% (95% CI = 26.4–40.3%) for with eventual brain metastasis, 33 had TNBC, and 1 had HR- noncarriers (Fig. 2). In the competitive risk analysis, the cumulative positive/HER2-negative primary breast cancer, though this incidence of brain metastasis was not different between the patient’s disease lost ER/PR expression at the time of distant gBRCA1 and noncarrier cohorts (P = 0.263 by Gray’s test). recurrence. Since the gBRCA1 cohort had the higher incidence of The brain parenchyma was a more frequent site of initial brain metastases and primarily TNBC, gBRCA noncarriers with recurrence in gBRCA1 patients versus noncarriers (20/76 [26.3%] TNBC and distant metastasis were utilized as the comparator vs. 22/182 [12.1%], P = .01 by Fisher’s exact test between the two group. groups). Brain metastases were diagnosed as the initial recurrence Breast cancer was diagnosed at a younger age in gBRCA1 in the absence of extracranial disease (i.e., isolated brain patients compared to gBRCA2 patients and noncarriers (median parenchymal metastases) in 11 of 20 gBRCA1 patients and 9 of age 38 vs. 44.8 vs. 47, P < 0.0001). The median time to genetic 22 noncarriers. Among patients with brain metastasis, approxi- testing was shorter in gBRCA1 patients than in gBRCA2 patients mately one-third of gBRCA1 and noncarrier patients had a solitary brain metastasis whereas 13 of 34 (38.2%) gBRCA1 patients, 6 of 7 and noncarriers (median 3.1 vs. 10.3 vs. 8.1 months, P = 0.029). (85.7%) of gBRCA2 patients, and 32 of 65 (49.2%) noncarriers had Diagnosis of a second primary breast tumor occurred in 5 of 76 more than three brain metastases on the initial brain MRI. The (6.5%) gBRCA1 patients, 5 of 42 (11.9%) of gBRCA2 patients, and 13 treatments administered for brain metastasis included whole- of 182 (7.1%) of noncarriers. Additional patient and disease brain radiotherapy (WBRT), stereotactic radiosurgery or radio- characteristics including patient race, cancer stage, tumor grade, therapy (SRS/SRT), and surgical resection. There were no large and tumor histology are listed in Table 1. differences in the modalities selected for gBRCA1 patients versus noncarriers. The median overall survival (OS) from the time of brain metastasis detection was uniformly poor: 7.8 months in gBRCA1 patients, 26.6 months in gBRCA2 patients, and 6.2 months *ns by log-rank in noncarriers (Fig. 3). The presence of brain metastasis, irrespective of its timing, adversely impacted OS (Fig. 4 and Supplementary Figure 1). For example, the 45 patients who had brain metastases detected at 50 the time of first recurrence had a median OS of 2.5 years gBRCA1 (n=473) compared to 3.4 years for patients who did not have brain gBRCA2 (n=318) metastases at the time of initial recurrence (HR 1.68, 95% CI 1.12–2.53). A similar trend was seen within the gBRCA1 cohort (Supplementary Figure 2). Lastly, we assessed potential clinical predictors of brain 0 5 10 15 20 metastasis among gBRCA1 and noncarrier patients in a multi- Time Since Diagnosis (years) variable logistic regression model. Univariate analyses were Number at risk: performed and variables with P ≤ .1 (breast cancer subtype, gBRCA1 473 300 172 94 53 presence of a second primary breast tumor, tumor grade, adjuvant gBRCA2 318 232 110 58 33 radiation) were then included in a multivariable model (Table 4; Supplementary Tables 1a/1b). In the multivariable model, TNBC Fig. 1 Distant metastasis-free survival. Distant metastasis-free was associated with higher rates of brain metastasis versus other survival for patients diagnosed with stage I-III breast cancer by gBRCA status. breast cancer subtypes, which was expected and biased by our npj Breast Cancer (2022) 46 Published in partnership with the Breast Cancer Research Foundation 1234567890():,; Distant metastasis-free survival H.R. Garber et al. Table 1. Clinical characteristics of patients with distantly recurrent breast cancer by germline BRCA status. BRCA Status germline BRCA1 germline BRCA2 BRCA1/2 non-carrier with P pathogenic variant pathogenic variant TNBC (n = 182) (n = 76) (n = 42) Clinical characteristic Median age at diagnosis (range) 38 (23–72) 44.8 (27–76) 47 (19–79) <0.0001 Median time from diagnosis to hereditary genetic 3.1 (0.8–16) 10.3 (1.2–114.1) 8.1 (1.8–28.1) 0.029 testing (IQR) in months No. of Patients % No. of Patients % No. of Patients % Sex Female 76 100 39 92.9 182 100 Male 3 7.1 Race White 41 53.9 32 76.2 118 64.8 <0.0001 Black 15 19.7 3 7.1 31 17.0 Hispanic 13 17.1 3 7.1 24 13.2 Asian/Pacific Islander 5 6.6 4 9.5 6 3.3 Other 2 2.6 3 1.6 Breast cancer subtype* TNBC 59 77.6 4 9.5 178 97.8 <0.0001 HR-positive/HER2-negative 8 10.5 30 71.4 HER2-positive 3 3.9 5 11.9 HR-positive/HER2 unknown 2 2.6 3 7.1 HR-negative/HER2 unknown 2 2.6 4 2.2 Unknown 2 2.6 2nd primary breast cancer 5 6.6 5 11.9 13 7.1 0.532 Stage (anatomic) 1 16 21.1 11 26.2 18 9.9 0.027 2 29 38.2 18 42.9 91 50.0 3 29 38.2 13 31.0 73 40.1 Unknown 2 2.6 Tumor grade 1 3 3.9 2 1.1 <0.0001 2 12 15.8 20 47.6 18 9.9 3 56 73.7 20 47.6 157 86.3 Unknown 5 6.6 2 4.8 5 2.7 Histology IDC 71 93.4 36 85.7 163 89.6 <0.0001 ILC 1 1.3 5 (mixed IDC/ILC) 11.9 4 (3 are mixed IDC/ 2.2 ILC) Other or breast cancer, NOS 3 3.9 1 2.4 15 8.2 Unknown 1 1.3 *For patients with a second primary breast cancer, the most recent subtype is listed. inclusion of noncarriers with TNBC only. Importantly, the model and gBRCA1. There was no difference in predilection to extra produced similar results with the breast cancer subtype variable cranial metastasis between gBRCA1 or gBRCA2 but revealed less incidence and longer time to brain metastasis of the tumors that removed (Supplemental Table 2). In addition, the odds ratio for brain metastasis among patients having received prior adjuvant are gBRCA2 mutated compared to those that are gBRCA1 mutated or non BRCA mutated TN breast cancer tumors. Among gBRCA1 radiation for a primary breast cancer versus no adjuvant radiation was 2.3 (95% CI 1.26–4.19, P = .0066). patients diagnosed with stage I-III breast cancer, 76 of 473 (16%) patients experienced a distant recurrence, and 34 of these 76 (44.7%) patients were diagnosed with brain metastases. The DISCUSSION frequency of brain metastasis among gBRCA2 patients with a Our study of breast cancer patients with hereditary pathogenic distant recurrence was lower, with brain metastases detected in 7 variants in gBRCA1 or gBRCA2 revealed a high frequency of brain of 42 (16.7%) gBRCA2 patients in our cohort. As a comparator metastasis among women with distantly recurrent breast cancer group for the gBRCA1 cohort, we utilized patients diagnosed with Published in partnership with the Breast Cancer Research Foundation npj Breast Cancer (2022) 46 H.R. Garber et al. Table 2. Treatment characteristics of patients with distantly recurrent breast cancer by germline BRCA status. BRCA Status germline BRCA1 germline BRCA2 BRCA1/2 noncarrier with P pathogenic variant pathogenic variant TNBC (n = 182) (n = 76) (n = 42) No. of Patients % No. of Patients % No. of Patients % Treatment characteristic* Surgery type Partial mastectomy 16 21 8 19 66 36 0.04 Mastectomy 57 75 34 81 112 62 ALND only for occult breast primary 0 0 0 0 2 1 Unknown 3 4 0 0 2 1 Chemotherapy Neoadjuvant 40 53 15 36 97 53 0.0001 Adjuvant 13 17 16 38 66 36 No chemotherapy 14 18 7 17 5 3 Neoadjuvant + adjuvant 9 12 4 10 14 8 Chemotherapy regimen Anthracycline-based (non-taxane) 12 17 8 21 27 14 Anthracycline + taxane 46 65 23 59 135 71 Taxane based 8 11 6 15 23 12 else 5 7 2 5 6 3 Radiation therapy Yes 47 62 30 71 126 69 0.677 No 26 34 12 29 56 31 Unknown 3 4 0 0 0 0 *For patients with a second primary breast cancer, the treatment for the most recent breast cancer is listed. These patients primarily received FAC chemotherapy. stage I-III TNBC with recurrent breast cancer who had tested considered as an initial event or at any time during the disease course. negative for variants in BRCA1 and BRCA2. In a competitive risk We were interested in the baseline risk of brain metastasis analysis using death as a competing risk factor, the cumulative among gBRCA1 and gBRCA2 patients in the pre-PARP inhibitor era incidence of brain metastasis did not differ between gBRCA1 to serve as context for evaluating CNS recurrences and responses patients and TNBC noncarrier patients. In addition, the time from now that PARP inhibitors and PARP inhibitors combinations are primary breast cancer diagnosis to the detection of brain increasingly utilized in the adjuvant and metastatic settings . metastasis was similar between gBRCA1 patients and TNBC PARP inhibitors improve systemic disease control and progression- noncarriers (2.4 vs. 2.2 years). One difference was that the brain free survival (an OS benefit has not been shown) versus standard was a more common site of initial distant recurrence in gBRCA1 chemotherapy, including in patients with treated brain metas- patients versus TNBC noncarriers (26.3% vs. 12.1%). In a multi- tases; however, their overall efficacy in the CNS remains uncertain. variable logistic regression model, aside from TNBC subtype, only Two other institutions have reported their experience with gBRCA the receipt of prior adjuvant radiation (vs. no prior adjuvant breast cancer patients and CNS recurrence. The Dana Farber radiation) for primary breast cancer treatment was associated with Cancer Institute (DFCI)/Beth Israel Deaconess Medical Center the eventual development of brain metastasis. We postulate that (BIDMC) gBRCA cohort has been the focus of several important this is likely related to more aggressive primary tumors, those with 10,11,20 reports . Lee et al. studied 46 gBRCA1 and 71 BRCA noncarrier a greater propensity to recur, being dispositioned to adjuvant early-stage breast cancer patients who had received alkylating radiation rather than due to untoward direct genotoxic effects chemotherapy and found that the rate and distribution of distant from the radiation itself on residual tumor cells. Our multivariable 20 metastasis and OS was similar between the two groups . They model did not consider variables such as tumor stage/nodal stage reported a potential propensity for brain metastasis among (we included overall anatomic stage), proliferation index (Ki-67), gBRCA1 patients (7 of 12 [58%] gBRCA1 patients with brain margin status, and lymphovascular invasion, which may explain metastasis vs. 5 of 21 (24%) noncarriers), which they examined in why the adjuvant radiation variable was significantly associated further detail in a follow-up report. This study included additional with brain metastasis in our model. patients (a total of 89 gBRCA1 and 175 noncarriers) and again Patient survival after the detection of brain metastasis was compared the clinical outcomes of early-stage breast cancer expectedly poor across subgroups and was only 7.8 months for patients treated with chemotherapy based on gBRCA1 status, gBRCA1 patients and 6.2 months in TNBC noncarriers. Survival limiting the analyses to the TNBC subtype. No difference was after brain metastasis was longer in gBRCA2 patients (2.2 years), observed between the two groups in terms of recurrence site, though interpretation of these data is limited by the small cohort freedom from distant metastasis, or breast cancer-specific survival. size (n = 7 patients). Brain metastasis had an adverse impact on The frequency of brain metastasis in gBRCA1 patients with a survival in comparison to other sites of distant metastasis when distant breast cancer recurrence in this study was 7 of 19 (36.8%) npj Breast Cancer (2022) 46 Published in partnership with the Breast Cancer Research Foundation H.R. Garber et al. Table 3. Characteristics of brain metastases in patients with distantly recurrent breast cancer by germline BRCA status. BRCA Status germline BRCA1 germline BRCA2 BRCA1/2 noncarrier P pathogenic variant pathogenic variant with TNBC (n = 76) (n = 42) (n = 182) No. of %No.of %No.of % Patients Patients Patients Breast cancer brain metastases detected at any time during patient’s course Yes 34 44.7 7 16.7 65 35.7 0.009 No 42 55.3 35 83.3 117 64.3 Median time to detection of brain metastases (years from date of 2.4 (0.7–31.9) 4.98 (1.7–14.4) 2.2 (0.5–6.5) 0.12 diagnosis, range) Was the brain a site of initial distant recurrence? Yes 20 26.3 3 7.1 22 12.1 0.058 No, brain mets were found later in course 14 18.4 4 9.5 43 23.6 No brain mets 42 55.3 35 83.3 117 64.3 If brain mets were among the initial site(s) of distant recurrence, was 0.53 extracranial disease absent or present at the time of recurrence? Extracranial disease absent 11 1 9 0.587 Extracranial disease present 9 2 13 Number of brain metastases at time of initial detection (as a %age of patients w/brain metastasis) solitary 12 35.3 1 14.3 21 32.3 0.2501 2–3 brain metastases 8 23.5 11 16.9 >3 brain metastases 13 38.2 6 85.7 32 49.2 unknown 1 2.9 1 1.5 Treatment for initial brain metastases* WBRT 22 56.4 4 50 36 48.6 SRS/SRT 8 20.5 25 33.8 Resection 8 20.5 2 25 10 13.5 Hospice 1 2.6 2 25 3 4.1 Unknown *Many patients were treated with multimodality therapy (e.g., resection followed by either SRS or WBRT). All treatments administered for the patients’ initial presentation of brain metastases are listed. BRCA1 Neg gBRCA1 (n=34) gBRCA2 (n=7) non-carriers (n=65) *ns by log-rank Gray's test P−value=0.263 0.0 2.5 5.0 Time Since Detection of Brain Metastasis (years) 0 5 10 15 20 25 30 35 Number at risk: gBRCA1 34 7 3 Time from diagnosis (years) gBRCA2 7 3 2 Fig. 2 Cumulative incidence of brain metastasis. Estimates of the non-carrier 65 8 2 cumulative incidence of brain metastasis are shown for gBRCA1 Fig. 3 Overall Survival with brain metastasis. Overall survival from patients (n = 76) and noncarriers with triple negative breast cancer the time of brain metastasis detection for breast cancer patients by (n = 182) diagnosed with stage I-III disease with subsequent distant gBRCA status. recurrence. Published in partnership with the Breast Cancer Research Foundation npj Breast Cancer (2022) 46 cumulative incidene for brain metastasis 0.0 0.2 0.4 0.6 0.8 1.0 Percent survival H.R. Garber et al. brain metastases are a site of initial gBRCA2 as a risk factor for brain metastasis compared to distant recurrence, n=45 100 noncarriers, our comparator group included only patients with brain metastases are not among the TNBC, whereas gBRCA2 breast cancer is predominantly HR+, and site(s) of initial distant recurrence,n=255 so our data do not address that specific question. A smaller study from Gustave Roussy reported parenchymal *P=.0018 by log-rank brain metastasis among patients with distantly recurrent breast cancer in 10/15 (66.7%) gBRCA1 patients, 0/12 gBRCA2 patients, and 6/58 (10.3%) noncarriers (all breast tumor subtypes included) . Taken together, these reports from the DFCI/BIDMC and Gustave Roussy along with our data from MDACC confirm a high rate of brain metastasis among gBRCA1 patients and 05 10 noncarriers with TNBC. There is no clear signal from the clinical Time Since Diagnosis (years) Number at risk: data that gBRCA breast cancers have a unique predilection for the brain met at CNS, especially when compared to patients with TNBC, though it is initial recurrence 45 12 1 plausible that different biologic mechanisms account for the high no brain met at initial recurrence 255 90 41 rate of CNS invasion in gBRCA1 versus noncarrier TNBC recurrences. Investigators have studied brain metastasis in other Fig. 4 Overall Survival with distant recurrence. Overall survival BRCA-associated malignancies. Data from small cohorts suggest from the time of diagnosis for patients with recurrent breast cancer that gBRCA ovarian cancer patients may be at a higher risk for stratified by the presence or absence of brain metastases among the initial sites of disease recurrence. brain metastasis (or isolated brain metastasis), though the overall rate (~2.5%) is far lower than seen in breast cancer. Alternatively, those data may be explained by longer overall survival in gBRCA ovarian cancer patients attributable to enhanced chemosensitivity Table 4. Multivariable logistic regression of potential clinical factors in 21–26 and effective PARP inhibitor maintenance therapy . Brain brain metastasis (n = 258 gBRCA1 and non-carrier patients). metastasis in gBRCA pancreatic cancer patients is case reportable 27–29 Effect Odds Ratio 95% Wald and is similarly rare in metastatic prostate cancer . Estimates Interestingly, increased homologous recombination deficiency Confidence Limits p- (in wild-type BRCA1/2 tumors) has been observed among breast value 30,31 cancer brain metastases . In one study that examined the Tumor grade (III vs. I/II) 2.425 0.971 6.055 0.0579 molecular features of paired primary breast tumors/brain metas- tases, an increase in homologous recombination deficiency was Breast ca subtype (others 0.082 0.01 0.636 0.0167 observed in the brain metastasis compared to the primary tumor vs TNBC) in 14/16 (87.5%) of the cases . Similar data have been reported Presence of a second 0.25 0.053 1.186 0.081 for colorectal cancer brain metastases . The investigators primary tumor hypothesize that higher levels of homologous recombination Adj radiation (Yes vs. no) 2.296 1.261 4.181 0.0066 deficiency may enable tumor cells to adapt more readily to the CNS microenvironment. In a systematic review of the genetic landscape of breast cancer brain metastases, several genes involved in DNA damage repair were among the 22 most patients and was 11 of 40 (27.5%) for noncarriers . Our analysis of frequently altered genes in brain metastases, including BRCA1, the MDACC cohort generally agrees with these data in demon- BRCA2, MLH1, ATR, ATM, and CHEK2 whereas these genes were not strating that the cumulative incidence of brain metastasis among among the most altered genes cataloged in extracranial distant gBRCA1 and TNBC patients is similarly high. When we modified the 33–35 recurrences . Accordingly, two genes integral to homologous competitive risk analysis to include only gBRCA1 patients who had recombination, BARD1, and RAD51, were found to be over- TNBC primary tumors (rather than other subtypes), the cumulative expressed in breast cancer brain metastases compared to incidence of brain metastasis was significantly higher among matched primary breast tumors, and when overexpressed in a gBRCA1 TNBC patients vs. noncarrier TNBC patients (Supplemen- human breast cancer cell line, these genes mediated increased tary Figure 3). brain metastases in mouse xenograft models . No studies have In a recent analysis of the DFCI gBRCA cohort, the authors focused exclusively on the molecular features of gBRCA brain reported a frequency of CNS metastasis (including parenchymal metastases, and it would be interesting to determine whether and leptomeningeal disease) among patients with recurrent these tumors undergo less genomic evolution upon CNS invasion breast cancer of 16/30 (53%) in gBRCA1 patients, 16/32 (50%) in since homologous recombination deficiency is intrinsic to the gBRCA2 patients, and 67/270 (25%) in noncarriers (including all primary tumor. In addition, if TNBC tumors do become more breast tumor subtypes, >50% HR+/HER2-negative) . In a multi- BRCA-like upon seeding the brain, there is the possibility for variable model within their study, only gBRCA2 was significantly therapeutic activity of PARP inhibitors with adequate CNS associated with CNS metastasis. The frequency of reported CNS penetration. For example, it will be important to assess whether metastasis in their gBRCA2 cohort was higher than in ours [16/32 olaparib, as evaluated in the phase III OlympiA trial, was effective 19,37 (50%) vs. 7/42 (16.7%)]. Both DFCI and MDACC are subject to at preventing both systemic and CNS recurrences . referral bias though differences in the timing of referral may be Our study has several limitations. First, gBRCA patients with one factor that explains the discrepancy. A second factor is that early-stage breast cancer have a good prognosis and, fortunately, 38,39 our primary event of interest was parenchymal brain metastasis distant metastasis is infrequent . Of the 791 gBRCA early stage rather than combined parenchymal brain metastasis/leptomenin- breast cancer patients that were followed longitudinally at geal disease. A third difference is that Song et al. relied on two MDACC, ~15% developed a distant recurrence, and the overall databases, one that included only patients with recurrent breast frequency of brain metastasis in the total gBRCA cohort was ~5%. cancer whereas we utilized one prospectively maintained As a result, our single-institution cohort of gBRCA patients with database that included all patients referred for genetic testing. distantly recurrent breast cancer is small, though it is larger/ Lastly, the gBRCA2 cohorts were limited in size in both studies. comparable to those from previous reports. Second, the true With regard to the multivariable model in Song et al. that showed incidence of brain metastasis is unknown since routine brain MRI npj Breast Cancer (2022) 46 Published in partnership with the Breast Cancer Research Foundation Percent survival H.R. Garber et al. screening is not recommended and is typically reserved for surgery for primary breast cancer, chemotherapy delivered for primary breast cancer, distant recurrence and date if applicable, location of distant symptomatic patients. Thus, the estimates we provide almost recurrence, and brain metastasis and date of detection if applicable. Brain certainly underestimate the true incidence. Third, though the metastasis characteristics and the treatment administered for the initial brain clinical genetics database at MDACC is prospectively maintained metastases were also abstracted from patients’ charts. Patients with Stage IV and routinely updated, our study is retrospective in its scope and de novo metastatic disease were excluded. there are many uncontrolled factors including date of gBRCA Tumors were considered triple negative if both ER and PR were negative testing, receipt and type of chemotherapy, and length of follow- (<10% tumor staining) and HER2 was considered non-amplified. up. A minor fraction of patients in all groups were lost to follow- HER2 status was assessed by immunohistochemistry or fluorescence up. Nonetheless, the strengths of our study include its use of a in situ hybridization when indicated and considered positive or negative single, large database with comprehensive clinical annotation and on the basis of institutional cutoffs and guidelines that were current at the time of diagnosis. For tumor grade, composite histologic grade was used the manual verification of all clinical data reported. The MDACC when available and if unavailable, nuclear grade was used. For patients genetics clinic is an active and longitudinal program, reflected by with a second primary breast cancer, the most recent primary breast the ~9-year median length of follow-up for gBRCA patients. As a cancer was used in the analysis. result, we believe the data provided in this report are representative of the larger gBRCA population. Statistical analyses In conclusion, brain metastasis is a similarly frequent event Continuous variables are reported as mean or median (and range or among gBRCA1 patients and gBRCA noncarriers with recurrent interquartile range [IQR]). The distribution of each categorical variable is TNBC. In a competitive risk analysis from the time of primary summarized in terms of its frequency and percentage. Distant metastasis- breast cancer diagnosis, the 5-yr cumulative incidence of brain free survival was defined as the time from primary breast cancer diagnosis metastasis among patients with recurrent breast cancer was 38.8% to distant metastasis (bone, liver, lung, CNS parenchyma, non-regional for gBRCA1 patients and 33.3% for noncarriers with TNBC (P = lymph node, etc.) or death from any cause. Patients still alive at the time of 0.26). Interestingly, studies of the molecular features of paired analysis were censored at their last date of follow-up. Time to brain primary breast cancer/brain metastasis specimens, most of which metastasis was computed from the date of diagnosis of the primary breast are BRCA1/2 wild-type, suggest that breast cancer cells capable of cancer to the date of detection of brain metastasis on imaging or last CNS propagation have increased homologous recombination follow-up. The cumulative incidence of brain metastases was estimated by deficiency, a characteristic intrinsic to BRCA1/2-deficient tumors. Fine-Gray competing risk approach, considering death as a competing risk . Among patients who developed brain metastasis, survival following The therapeutic efficacy of PARP inhibitors for the treatment or brain metastasis was computed from the date of detection of brain prevention of CNS recurrence in BRCA-mutant (hereditary or metastasis to the date of death or last follow-up. Categorical data were somatic) or BRCA wild-type breast cancer is largely unknown, compared using the Χ or Fisher’s exact test. Continuous data were though the currently approved PARP inhibitors are unlikely to compared using Wilcoxon rank sum test (two groups) or Kruskal–Wallis test mediate durable CNS responses as monotherapy. Our study aligns (three groups). All tests were two-sided and P values < 0.05 were with prior reports and underscores the importance of improving considered statistically significant as exploratory analyses. We used the the prevention and treatment of brain metastasis in patients with Kaplan–Meier method to estimate survival and compared survival curves recurrent TNBC, both in gBRCA1 carriers and noncarriers. using the log-rank test. Computations were carried out using SAS version 9.4 and R 4.0.2 and GraphPad Prism 8. METHODS Reporting summary Patient population and data collection Further information on research design is available in the Nature Research Approval was obtained from the institutional review board at UT MD Reporting Summary linked to this article. Anderson Cancer Center (MDACC, approval no. PA18-0386). A waiver of consent was obtained to ensure ethical standards of data use due to the retrospective nature of the study. To determine the incidence of brain DATA AVAILABILITY metastasis among gBRCA patients and gBRCA noncarriers, we queried an The data that support the findings of this study are available from the corresponding IRB-approved, prospectively maintained electronic database that includes author, upon reasonable request. patients referred to the MDACC clinical cancer genetics program who underwent gBRCA testing. Patients who test positive for various germline Received: 29 September 2021; Accepted: 24 February 2022; mutations or negative (noncarriers) are included in the database. We identified patients within the database with stage I-III invasive breast cancer who were evaluated at MDACC between 2000-2017 and who tested positive for hereditary mutations in BRCA1 or BRCA2 and assessed for disease recurrence and parenchymal brain metastasis. Patients with variants of uncertain significance in gBRCA were excluded from the REFERENCES analysis. 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Increased incidence of visceral metastases in scottish patients The authors declare no competing interests. with BRCA1/2-defective ovarian cancer: an extension of the ovarian BRCAness phenotype. J. Clin. Oncol. 28, 2505–2511 (2010). 23. Sekine, M. et al. Increased incidence of brain metastases in BRCA1-related ovarian ADDITIONAL INFORMATION cancers. J. Obstet. Gynaecol. Res. 39, 292–296 (2013). Supplementary information The online version contains supplementary material 24. Stasenko, M. et al. Brain metastasis in epithelial ovarian cancer by BRCA1/2 available at https://doi.org/10.1038/s41523-022-00407-z. mutation status. Gynecol. Oncol. 154, 144–149 (2019). 25. Ratner, E. et al. Increased risk of brain metastases in ovarian cancer patients with Correspondence and requests for materials should be addressed to Nuhad K. BRCA mutations. Gynecol. Oncol. 153, 568–573 (2019). Ibrahim. 26. Balendran, S. et al. 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Clinical, genetic, and pathologic determinants of prostate cancer Open Access This article is licensed under a Creative Commons brain metastasis. J. Clin. Oncol. 38, 5536–5536 (2020). Attribution 4.0 International License, which permits use, sharing, 30. Diossy, M. et al. Breast cancer brain metastases show increased levels of genomic adaptation, distribution and reproduction in any medium or format, as long as you give aberration-based homologous recombination deficiency scores relative to their appropriate credit to the original author(s) and the source, provide a link to the Creative corresponding primary tumors. Ann. Oncol. 29, 1948–1954 (2018). Commons license, and indicate if changes were made. The images or other third party 31. Tyran, M. et al. A comparison of DNA mutation and copy number profiles of material in this article are included in the article’s Creative Commons license, unless primary breast cancers and paired brain metastases for identifying clinically indicated otherwise in a credit line to the material. If material is not included in the relevant genetic alterations in brain metastases. Cancers 11, 5 (2019). article’s Creative Commons license and your intended use is not permitted by statutory 32. Sun, J. et al. Genomic signatures reveal DNA damage response deficiency in regulation or exceeds the permitted use, you will need to obtain permission directly colorectal cancer brain metastases. Nat. Commun. 10, 3190 (2019). from the copyright holder. To view a copy of this license, visit http://creativecommons. 33. Morgan, A. J., Giannoudis, A. & Palmieri, C. The genomic landscape of breast org/licenses/by/4.0/. cancer brain metastases: a systematic review. Lancet Oncol. 22,e7–e17 (2021). 34. Bertucci, F. et al. Genomic characterization of metastatic breast cancers. Nature 569, 560–564 (2019). © The Author(s) 2022 npj Breast Cancer (2022) 46 Published in partnership with the Breast Cancer Research Foundation

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