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BRCAness Combined With a Family History of Cancer Is Associated With a Poor Prognosis for Breast Cancer Patients With a High Risk of BRCA Mutations

Open AccessPublished:June 01, 2018DOI:https://doi.org/10.1016/j.clbc.2018.05.008

      Abstract

      Background

      The inexpensive prediction of the characteristics of BRCA-mutated breast cancer as “BRCAness” using the somatic cells of patients with breast cancer could be useful for developing a therapeutic strategy. Our objective was to correlate BRCAness with the clinicopathologic features, including a family history (FH) of cancer, in breast cancer patients with a high risk of BRCA mutations.

      Patients and Methods

      The present study included 124 patients, including 55 with early-onset and 77 with triple-negative breast cancer, who had undergone resection at Kyushu University Hospital from 2005 to 2014. Early-onset breast cancer is defined as an onset in patients aged ≤ 40 years. BRCAness was performed using multiple ligation-dependent probe amplification. The patients’ FH of cancer was surveyed from first- to third-degree relatives.

      Results

      Of the 124 patients, the multiple ligation-dependent probe amplification assay results indicated that 59 tumors (47.6%) had BRCAness and 27 patients (21.8%) had a positive FH for cancer. The patients with BRCAness experienced significantly shorter recurrence-free survival (RFS) and overall survival (OS) compared with those without. Patients with FH had shorter RFS and OS compared to those without BRCAness. The patients were divided into those with and without BRCAness and those with and without a positive FH. The BRCAness with FH subgroup experienced significantly shorter RFS and OS. Multivariate analysis revealed that BRCAness and a positive FH were independent negative prognostic factors.

      Conclusion

      Our findings suggest that BRCAness tumors with a positive FH of cancer were associated with a poor prognosis in the BRCA-mutation high-risk group. We propose that BRCAness and a positive FH will serve to predict patients’ prognosis.

      Keywords

      Introduction

      Breast cancer is the most frequent cancer of women worldwide. In Japan, the breast cancer incidence in 2013 was 76,839 and the cumulative incidence risk was 9% (1 of 11 Japanese women).
      • Cancer Registry and Statistics
      Cancer Information Service, National Cancer Center, Japan.
      Hereditary breast cancer accounts for 5% to 10% of breast cancer cases, and BRCA1 and BRCA2 are the most common causes of the hereditary forms of breast and ovarian cancer. Hereditary breast and ovarian cancer (HBOC) syndrome, which is associated with BRCA1 or BRCA2, is characterized by an increased risk of breast cancer and ovarian cancer. In the case of individuals with a BRCA2 pathogenic variant, HBOC is also associated with an increased risk of pancreatic cancer and prostate cancer, although with a lower frequency than that of breast and ovarian cancer.

      Petrucelli N, Daly MB, Pal T. BRCA1- and BRCA2-associated hereditary breast and ovarian cancer. GeneReviews Initial posting September 4, 1998; updated December 15, 2016.

      Clues to the identification of HBOC syndrome include the personal and family history (FH). The characteristics that can provide a clue to HBOC syndrome include early-age onset of breast cancer, multiple primary breast cancers (synchronous or asynchronous bilateral disease or more clearly separated ipsilateral tumors), and a specific tumor type. The characteristics within a family include multiple generations with a relatively high incidence of HBOC-related cancers, such as those of the breast, ovaries, pancreas, and prostate. Similar to a personal history of cancer, a family with a history of early-onset breast cancer increases the likelihood of HBOC.
      A major risk factor for HBOC is the development of breast cancer at an early age. According to Knudson’s “2-hit” theory,
      • Knudson Jr., A.G.
      Mutation and cancer: statistical study of retinoblastoma.
      a dominantly inherited predisposition to cancer entails a germline mutation, with tumorigenesis requiring a second somatic mutation. Nonhereditary cancer of the same type requires the same 2 hits; however, both are somatic mutations. If a patient has a germline mutation in 1 of the genes, only “1 hit” would cause oncogenesis, and these tumors typically occur in younger patients. Thus, an early age at diagnosis is considered a potential indicator of an underlying genetic predisposition for breast cancer. Approximately 2% to 3% of Japanese women with breast cancer are diagnosed when they are aged < 40 years,
      • Cancer Registry and Statistics
      Cancer Information Service, National Cancer Center, Japan.
      and this disease accounts for ≥ 30% of all cancer in women in this age group. Breast cancer in women aged < 40 years is relatively uncommon and has been associated with lower survival rates compared with women aged > 40 years.
      • Cancer Registry and Statistics
      Cancer Information Service, National Cancer Center, Japan.
      BRCA1-mutated breast cancer most often exhibits the phenotype of triple-negative breast cancer (TNBC), which is defined by undetectable levels of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2).
      • Lee E.
      • McKean-Cowdin R.
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      • et al.
      Characteristics of triple-negative breast cancer in patients with a BRCA1 mutation: results from a population-based study of young women.
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      The prevalence of BRCA1 mutations among young women with triple-negative breast cancer.
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      • Lopez A.
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      Clinical and pathologic characteristics of patients with BRCA-positive and BRCA-negative breast cancer.
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      Prediction of BRCA1 status in patients with breast cancer using estrogen receptor and basal phenotype.
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      • et al.
      Relationship of patients' age to histopathological features of breast tumours in BRCA1 and BRCA2 and mutation-negative breast cancer families.
      BRCA1 mutations occur in 8.5% to 28% of patients with TNBC.
      • Young S.R.
      • Pilarski R.T.
      • Donenberg T.
      • et al.
      The prevalence of BRCA1 mutations among young women with triple-negative breast cancer.
      • Tung N.
      • Lin N.U.
      • Kidd J.
      • et al.
      Frequency of germline mutations in 25 cancer susceptibility genes in a sequential series of patients with breast cancer.
      • Evans D.G.
      • Howell A.
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      • et al.
      Prevalence of BRCA1 and BRCA2 mutations in triple negative breast cancer.
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      • Papadimitriou C.
      • et al.
      Prevalence of BRCA1 mutations among 403 women with triple-negative breast cancer: implications for genetic screening selection criteria: a Hellenic Cooperative Oncology Group Study.
      • Gonzalez-Angulo A.M.
      • Timms K.M.
      • Liu S.
      • et al.
      Incidence and outcome of BRCA mutations in unselected patients with triple receptor-negative breast cancer.
      • Rummel S.
      • Varner E.
      • Shriver C.D.
      • et al.
      Evaluation of BRCA1 mutations in an unselected patient population with triple-negative breast cancer.
      • Couch F.J.
      • Hart S.N.
      • Sharma P.
      • et al.
      Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer.
      A meta-analysis found that women with TNBC are significantly more likely to carry a BRCA1 mutation than women with breast cancer not classified as TNBC (relative risk [RR], 5.65; 95% confidence interval [CI], 4.15-7.69).
      • Tun N.M.
      • Villani G.
      • Ong K.
      • et al.
      Risk of having BRCA1 mutation in high-risk women with triple-negative breast cancer: a meta-analysis.
      In contrast, the frequencies of BRCA2 mutations range from 1% to 17% in studies of TNBC cases unselected for age or positive FH.
      • Tung N.
      • Lin N.U.
      • Kidd J.
      • et al.
      Frequency of germline mutations in 25 cancer susceptibility genes in a sequential series of patients with breast cancer.
      • Evans D.G.
      • Howell A.
      • Ward D.
      • et al.
      Prevalence of BRCA1 and BRCA2 mutations in triple negative breast cancer.
      • Couch F.J.
      • Hart S.N.
      • Sharma P.
      • et al.
      Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer.
      • Meyer P.
      • Landgraf K.
      • Hogel B.
      • et al.
      BRCA2 mutations and triple-negative breast cancer.
      Furthermore, among patients with TNBC, carriers of BRCA mutations will have breast cancer diagnosed at a younger age compared with noncarriers.
      • Gonzalez-Angulo A.M.
      • Timms K.M.
      • Liu S.
      • et al.
      Incidence and outcome of BRCA mutations in unselected patients with triple receptor-negative breast cancer.
      BRCA1 and BRCA2 are crucial for homologous recombination repair of DNA, and these hallmarks have been termed “BRCAness,” defined as traits that certain sporadic cancers share with carriers of BRCA mutations.
      • Turner N.
      • Tutt A.
      • Ashworth A.
      Hallmarks of “BRCAness” in sporadic cancers.
      BRCAness tumors are highly sensitive to chemotherapy using DNA-damaging agents
      • Lips E.H.
      • Laddach N.
      • Savola S.P.
      • et al.
      Quantitative copy number analysis by multiplex ligation-dependent probe amplification (MLPA) of BRCA1-associated breast cancer regions identifies BRCAness.
      or high-doses of platinum.
      • Vollebergh M.A.
      • Lips E.H.
      • Nederlof P.M.
      • et al.
      An aCGH classifier derived from BRCA1-mutated breast cancer and benefit of high-dose platinum-based chemotherapy in HER2-negative breast cancer patients.
      • Vollebergh M.A.
      • Lips E.H.
      • Nederlof P.M.
      • et al.
      Genomic patterns resembling BRCA1- and BRCA2-mutated breast cancers predict benefit of intensified carboplatin-based chemotherapy.
      Also, BRCAness serves as an essential biomarker for predicting the prognosis of those with TNBC.
      • Mori H.
      • Kubo M.
      • Nishimura R.
      • et al.
      BRCAness as a biomarker for predicting prognosis and response to anthracycline-based adjuvant chemotherapy for patients with triple-negative breast cancer.
      A positive FH of cancer is a strong risk factor for the onset of breast cancer and is dependent on the frequency of breast cancer in the family. For instance, the pooled estimate of RR associated with various FH factors is as follows: mother, RR, 2.0; 95% CI, 1.8-2.1; mother and sister, RR, 3.6; 95% (CI, 2.1-2.4).
      • Pharoah P.D.P.
      • Day N.E.
      • Duffy S.
      • et al.
      Family history and the risk of breast cancer: a systematic review and meta-analysis.
      However, the association between a positive FH and mortality after the diagnosis of breast cancer is unclear in most Asian countries, because genetic examinations and surveillance were not available easily and inexpensively. Assessment of a patient’s risk of familial or hereditary breast cancer requires a thorough evaluation of the patient’s FH. An evaluation of the FH should include the first-, second-, and third-degree maternal and paternal relatives. The most important evaluation criteria include diagnoses according to the primary site (including bilaterality when appropriate), age at diagnosis, and incidence in maternal or paternal sides.
      Patients with breast cancer with such characteristics are likely to have HBOC and therefore require appropriate genetic counseling. In Japan, BRCA1/2 genetic testing is not covered by the national insurance program. Moreover, the number of patients incorporated into clinical practice has been limited because of the unavailability of genetic counselors (specifically for cancer) in certain institutions. The inexpensive prediction of the characteristics of BRCA-mutated breast cancer as “BRCAness” using the somatic cells of patients with breast cancer could be useful for developing a widely effective therapy for patients with BRCA-like breast cancer. Our objective was to correlate BRCAness with the clinicopathologic features, including a positive FH, in breast cancer patients with a high risk of BRCA mutations.

      Patients and Methods

      Patient History and FH

      The present study included all patients who had undergone surgery for primary breast cancer at Kyushu University Hospital from January 2005 to December 2014 (910 women and 4 men). To focus on the BRCA1/2-mutations high-risk group, the inclusion criteria (Figure 1) were a diagnosis of invasive breast cancer (n = 790), early-onset breast cancer (age ≤ 40 years) or TNBC (n = 140). Specimens (before and after neoadjuvant chemotherapy [NAC]) that were unavailable for tissue review were excluded (n = 16). We included 124 patients (all women; the 4 men were excluded because they were aged > 40 years and their tumor subtype was luminal). The 124 patients had the following characteristics: early-onset breast cancer (n = 47), TNBC (n = 69), and early-onset breast cancer coexisting with TNBC (n = 8). The BRCAness of these TNBCs was reported in our previous study.
      • Mori H.
      • Kubo M.
      • Nishimura R.
      • et al.
      BRCAness as a biomarker for predicting prognosis and response to anthracycline-based adjuvant chemotherapy for patients with triple-negative breast cancer.
      Patients received neoadjuvant or adjuvant treatment according to the following guidelines: National Comprehensive Cancer Network (NCCN) guidelines for the treatment of breast cancer,
      NCCN Clinical Practice Guidelines in Oncology, Breast Cancer, Version 3. 2017—November 10, 2017.
      Clinical Practice Guideline of Breast Cancer by the Japanese Breast Cancer Society,
      Clinical Practice Guideline of Breast Cancer by the Japanese Breast Cancer Society, version 3, 2015.
      and the recommendations of the St Gallen International Breast Cancer Conference.
      • Goldhirsch A.
      • Wood W.C.
      • Coates A.S.
      • et al.
      Strategies for subtypes—dealing with the diversity of breast cancer: highlights of the St. Gallen International Expert Consensus on the primary therapy of early breast cancer 2011.
      • Goldhirsch A.
      • Ingle J.N.
      • Gelber R.D.
      • et al.
      Thresholds for therapies: highlights of the St Gallen International Expert Consensus on the primary therapy of early breast cancer 2009.
      • Goldhirsch A.
      • Wood W.C.
      • Gelber R.D.
      • et al.
      Progress and promise: highlights of the international expert consensus on the primary therapy of early breast cancer 2007.
      • Goldhirsch A.
      • Glick J.H.
      • Gelber R.D.
      • et al.
      Meeting highlights: international expert consensus on the primary therapy of early breast cancer 2005.
      We conducted a survey to determine the presence of a positive FH for breast cancer, ovarian cancer, pancreatic cancer, and prostate cancer among first- to third-degree relatives with reference to the NCCN guidelines for genetic/familial high risk assessment: breast and ovarian, version 1, 2018.
      NCCN Clinical Practice Guidelines in Oncology. Genetic/familial high risk assessment: breast and ovarian, version 1. 2018—October 3, 2017.
      Figure thumbnail gr1
      Figure 1Patient Selection
      Abbreviations: NAC = neoadjuvant chemotherapy; TN = triple negative.
      The present study conformed to the principles of the Declaration of Helsinki, and the institutional review board (IRB) of Kyushu University Hospital approved the study (approval nos. 27-102, 28-189). Before surgery, the participants had provided comprehensive written consent, which stated that the tissue samples from the resected specimen could be used for research purposes. On IRB approval, all details were posted on the Kyushu University Hospital website instead of renewing the informed consent. All patients had the option to confirm ongoing studies and can choose to opt out of consent at any time. The IRB approved this consent procedure.

      Immunohistochemistry

      The tumor subtype was routinely determined using immunohistochemical analysis of the resected specimens, which were fixed (within 1 hour) in 10% neutral-buffered formalin for 6 to 72 hours. For patients administered NAC, the core needle biopsy specimens acquired before NAC were analyzed. ER+ and PR+ samples were defined by the detection of ER or PR expression in ≥ 1% of the tumor cells. The cancer specimens were defined as HER2+ when HER2 expression was scored as 3+ or if fluorescence in situ hybridization detected HER2 amplification.

      Multiple Ligation-dependent Probe Amplification

      Core needle biopsy specimens before NAC (n = 16) and surgical specimens (n = 108) were used for multiple ligation-dependent probe amplification (MLPA) analysis. DNA was isolated from formalin-fixed paraffin-embedded tumor tissues using a QIAamp DNA formalin-fixed paraffin-embedded tissue kit (Qiagen, Hilden, Germany). The classification of the BRCAness subtypes was performed using MLPA with a P376 BRCA1ness probe mix (MRC-Holland, Amsterdam, The Netherlands).
      • Lips E.H.
      • Laddach N.
      • Savola S.P.
      • et al.
      Quantitative copy number analysis by multiplex ligation-dependent probe amplification (MLPA) of BRCA1-associated breast cancer regions identifies BRCAness.
      MLPA determines the relative copy numbers of DNA sequences and was performed according to a previous report.
      • Schouten J.P.
      • McElgunn C.J.
      • Waaijer R.
      • et al.
      Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplification.
      The MLPA probe mixture contained 38 target probes, which constituted the most important genomic regions of the BRCA1-like classifier according to the specific aberrations of BRCA1-mutated breast cancer. The data were compared with those from sporadic tumors using array comparative genomic hybridization and 8 control reference probes.
      • Lips E.H.
      • Laddach N.
      • Savola S.P.
      • et al.
      Quantitative copy number analysis by multiplex ligation-dependent probe amplification (MLPA) of BRCA1-associated breast cancer regions identifies BRCAness.
      Data analysis was performed using the Coffalyser.NET software (MRC-Holland). The relative copy number ratio of each sample was compared using human genomic DNA (Promega, Madison, WI) as the reference. BRCAness scores were calculated using the relative copy number ratios of the DNA sequences. The relative copy number ratios from Coffalyser.NET for all target-specific probes were used in the prediction analysis of the microarrays. The training set generated by MRC-Holland with P376-B2 Lot 0911 was used for the prediction analysis of the microarrays. Each sample was analyzed twice, and the average score was used. The BRCAness analysis was performed by researchers completely uninformed of the clinical information. A sample with a BRCAness score of ≥ 0.5 was classified as BRCAness. If the score was < 0.5, the sample was classified as non-BRCAness.
      • Joosse S.A.
      • van Beers E.H.
      • Tielen I.H.
      • et al.
      Prediction of BRCA1-association in hereditary non-BRCA1/2 breast carcinomas with array-CGH.

      Statistical Analysis

      Logistic regression analysis was used to compare continuous variables, and the χ2 test was used to assess categorical variables. The survival endpoints were recurrence-free survival (RFS) and overall survival (OS). RFS was defined as the interval from surgery to recurrence, including local relapse and metastatic disease. OS was defined as the interval from surgery until the date of death from any cause. Survival curves were generated using the Kaplan-Meier method and were compared using the log-rank test. Hazard ratios were calculated using Cox proportional hazards regression. A value of P < .05 was considered statistically significant. Statistical analysis was performed using JMP, version 11 (SAS Institute Inc, Cary, NC).

      Results

      BRCAness and FH

      BRCAness was detected using the MLPA assay in the specimens from 59 of all 124 patients (47.6%), 19 of the 55 early-onset patients (34.5%), and 45 of the 77 TNBC patients (58.4%; Figure 2A). A positive FH was found for 27 of the 124 patients (21.8%), 16 of the 55 early-onset patients (29.1%), and 15 of the 77 TNBC patients (19.5%; Figure 2B). Of the variables analyzed for an association with BRCAness and non-BRCAness (Table 1), no significant differences were found regarding tumor size, nodal status, or pathologic stage. However, the nuclear grade and Ki-67 index of the BRCAness tumors were significantly greater than those of the non-BRCAness tumors (P < .0001 and P = .0006, respectively). BRCAness tumors included more TNBC cases compared with non-BRCAness tumors (P = .01). No correlation was found between the presence of BRCAness and a positive FH. In addition, the data from patients with and without a positive FH were analyzed with several other variables (Supplemental Table 1; available in the online version). Of these variables, the only significant difference was that patients with a positive FH were significantly younger than the patients without a positive FH (P = .04).
      Figure thumbnail gr2
      Figure 2Venn Diagrams of BRCAness and Family History (FH) in Early-Onset and Triple-Negative (TN) Breast Cancer Showing the Distribution of (A) BRCAness and (B) a Positive FH in Early-Onset and TN Breast Cancer
      Table 1Patient and Tumor Characteristics Stratified by BRCAness Status
      CharacteristicBRCAness (n = 59)Non-BRCAness (n = 65)P Value
      Age at diagnosis.11
      Logistic regression analysis.
       Mean52.447.9
       Range29-8125-84
      Tumor size.19
      Pearson's χ2 test.
       T1 (≤2 cm)26 (44.1)36 (55.4)
       T2 (>2 but ≤ 5 cm)28 (47.5)23 (35.4)
       T3 (>5 cm)3 (5.1)6 (9.2)
       T42 (3.4)0 (0)
      Nodal status.52
      Pearson's χ2 test.
       N041 (69.5)47 (72.3)
       N1 (1-3)13 (22.0)14 (21.5)
       N2 (4-9)3 (5.1)4 (6.2)
       N3 (≥10)2 (3.4)0 (0)
      Pathologic stage.51
      Pearson's χ2 test.
       I23 (39.0)29 (44.6)
       II29 (49.2)29 (49.2)
       III7 (11.9)4 (6.2)
      Nuclear grade< .0001
      Pearson's χ2 test.
      ,
      Statistically significant difference.
       111 (20.0)42 (68.9)
       27 (12.7)7 (11.5)
       337 (67.3)12 (19.7)
      Ki-67.0006
      Logistic regression analysis.
      ,
      Statistically significant difference.
       Mean48.121.0
       Range10-830-80
      Subtype.01
      Pearson's χ2 test.
      ,
      Statistically significant difference.
       Luminal11 (18.6)26 (40.0)
       Luminal/HER23 (5.1)4 (6.2)
       HER20 (0)3 (4.6)
       Triple negative45 (76.3)32 (49.2)
      Family history (FH).43
      Pearson's χ2 test.
      ,
      Statistically significant difference.
       With FH11 (18.6)16 (24.6)
       Without FH48 (81.4)49 (75.4)
      Data presented as mean and range or n (%).
      a Logistic regression analysis.
      b Pearson's χ2 test.
      c Statistically significant difference.
      Analysis of the tumor subtypes of the patients with early-onset breast cancer aged ≤ 40 years (Supplemental Table 2; available in the online version) revealed that patients with BRCAness tumors tended to more often have TNBC and less often to have luminal and HER2 cancer compared with patients with non-BRCAness tumors. Furthermore, the group with a positive FH tended to include more patients with TNBC and luminal/HER2 and fewer with luminal-positive and HER2+ types compared with patients without a positive FH (Supplemental Table 3; available in the online version).

      Survival

      The median follow-up was 67 months (range, 2-137 months). Patients with BRCAness tumors experienced significantly shorter RFS (P = .002; Figure 3A) and OS (P = .006; Figure 3B) compared with patients with non-BRCAness tumors. In contrast, patients with a positive FH experienced significantly shorter RFS (P = .03; Figure 3C) and OS (P = .02; Figure 3D) compared with patients without a positive FH. Next, we allocated the patients into 4 subgroups: BRCAness with a positive FH, BRCAness without a positive FH, non-BRCAness with a positive FH, and non-BRCAness without a positive FH. The Kaplan-Meier analysis demonstrated that RFS (P < .0001; Figure 4A) and OS (P < .0001; Figure 4B) differed significantly among the 4 subgroups. However, the treatment background for these 4 subgroups did not differ significantly.
      Figure thumbnail gr3
      Figure 3Prognostic Value of BRCAness and Family History (FH). Kaplan-Meier Analysis of Estimated (A) Recurrence-Free Survival (RFS) and (B) Overall Survival (OS) Associated With BRCAness and (C) RFS and (D) OS (D) Associated With FH. P Values From Comparisons of the 2 Groups
      Figure thumbnail gr4
      Figure 4Prognostic Value of the Combination of BRCAness and Positive Family History (FH). Kaplan-Meier Analysis of Estimated (A) Recurrence-Free Survival (RFS) and (B) Overall Survival (OS) for BRCAness/FH+, BRCAness/FH, non-BRCAness/FH+, and non-BRCAness/FH. P Values From Comparison of the 4 Subgroups

      Univariate and Multivariate Analyses of Survival

      Univariate analysis of the clinicopathologic characteristics revealed that tumors > 2 cm, lymph node involvement, TN status, BRCAness, and a positive FH were significantly associated with poorer RFS and OS (Table 2). Age at diagnosis, nuclear grade, and Ki-67 index were excluded from the multivariate analysis using a back-elimination method. Multivariate analysis revealed that BRCAness and FH were independent and negative prognostic factors for RFS and OS (Table 2).
      Table 2Cox Proportional Hazards Model for Recurrence-free and Overall Survival
      VariableRecurrence-free SurvivalOverall Survival
      HR95% CIP ValueHR95% CIP Value
      Univariate analysis
       Age (>40 vs. ≤ 40 y)2.20.9-6.1.102.10.7-7.9.19
       Tumor size (>2 cm vs. ≤ 2 cm)4.51.6-15.5.003
      Statistically significant difference.
      5.91.6-38.3.006
      Statistically significant difference.
       Nodal status (positive vs. negative)2.51.1-6.1.04
      Statistically significant difference.
      2.10.7-6.3.20
       Nuclear grade (3 vs. 1 and 2)1.80.7-4.8.212.00.7-6.9.22
       Ki-67 (>20% vs. ≤ 20%)2.40.5-16.9.271.90.2-40.3.61
       Subtype (TN vs. non-TN)4.21.4-18.0.009
      Statistically significant difference.
      9.11.8-167.005
      Statistically significant difference.
       BRCAness status (BRCAness vs. non-BRCAness)5.11.9-17.9.0009
      Statistically significant difference.
      6.41.7-41.6.004
      Statistically significant difference.
       Family history (positive vs. negative)2.71.1-6.4.04
      Statistically significant difference.
      3.71.2-11.4.03
      Statistically significant difference.
      Multivariate analysis
       Tumor size (>2 cm vs. ≤ 2 cm)2.91.1-10.3.03
      Statistically significant difference.
      3.60.9-23.9.07
       Nodal status (positive vs. negative)1.80.7-4.6.201.60.5-4.9.45
       Subtype (TN vs. non-TN)2.80.9-12.4.096.51.2-122.03
      Statistically significant difference.
       BRCAness status (BRCAness vs. non-BRCAness)4.01.4-14.6.01
      Statistically significant difference.
      4.81.2-32.2.03
      Statistically significant difference.
       Family history (positive vs. negative)2.81.1-7.1.04
      Statistically significant difference.
      4.51.3-14.8.02
      Statistically significant difference.
      Abbreviations: CI = confidence interval; HR = hazard ratio; TN = triple negative.
      a Statistically significant difference.

      Discussion

      For the present study, we selected patients who were more likely have hereditary breast cancer, as defined by the NCCN guidelines,
      NCCN Clinical Practice Guidelines in Oncology. Genetic/familial high risk assessment: breast and ovarian, version 1. 2018—October 3, 2017.
      and focused on early-onset breast cancer and TNBC. We assessed BRCAness as characteristics of BRCA-mutated breast cancer and investigated the patients’ FHs for breast cancer, ovarian cancer, pancreatic cancer, and prostate cancer. BRCAness accounts for 11% to 14% of sporadic breast cancers
      • Turner N.
      • Tutt A.
      • Ashworth A.
      Hallmarks of “BRCAness” in sporadic cancers.
      and 66% to 69% of TNBCs.
      • Lips E.H.
      • Mulder L.
      • Oonk A.
      • et al.
      Triple-negative breast cancer: BRCAness and concordance of clinical features with BRCA1-mutation carriers.
      Our results revealed that 34.5% of early-onset patients and 58.4% of TNBC patients had BRCAness. Although early-onset breast cancer includes TN and luminal and HER2 types (Supplemental Table 2; available in the online version), we noted that early-onset breast cancer was significantly associated with more BRCAness tumors compared with sporadic breast cancer.
      BRCAness is defined by factors such as low BRCA expression, BRCA-promoter methylation, and the presence of BRCA mutations. In a sample of 21,401 families who met the German Consortium for HBOC testing criteria for BRCA1/2 mutations, a mutation was detected in 13.7% of the families with a single case of breast cancer diagnosed before the members had reached 36 years of age.
      • Kast K.
      • Rhiem K.
      • Wappenschmidt B.
      • et al.
      Prevalence of BRCA1/2 germline mutations in 21 401 families with breast and ovarian cancer.
      Furthermore, 106 women with a BRCA mutation (generation 2) who participated in a high-risk protocol were compared with family members from the previous generation (generation 1) who had also had a BRCA-mutation–related cancer (breast or ovarian). In that study, the breast and ovarian cancers of the BRCA-mutation carriers were diagnosed at 42 years of age in generation 2 compared with 48 years of age in generation 1 (P < .001).
      • Litton J.K.
      • Ready K.
      • Chen H.
      • et al.
      Earlier age of onset of BRCA mutation-related cancers in subsequent generations.
      A genetic anticipation effect might exist in those with BRCA1/2 mutations, in that the age of disease onset might decrease. Thus, the NCCN guidelines recommend starting screening at age 20 to 25 years or at the age of the earliest breast cancer case in the family if diagnosed at age < 20 years.
      NCCN Clinical Practice Guidelines in Oncology. Genetic/familial high risk assessment: breast and ovarian, version 1. 2018—October 3, 2017.
      Studies of BRCAness are generally included in studies of TNBC. Therefore, only limited data are available that address all subtypes of breast cancer. For example, a BRCAness study of 45 core needle biopsy specimens of all tumor subtypes before neoadjuvant chemotherapy found 17 (23.3%) with BRCAness. The distribution was as follows: 14 (60.9%) with TNBC, 2 (28.6%) with HER2, 1 (7.7%) with ER+/HER2 expression, and none with ER+/HER2+.
      • Akashi-Tanaka S.
      • Watanabe C.
      • Takamaru T.
      • et al.
      BRCAness predicts resistance to taxane-containing regimens in triple negative breast cancer during neoadjuvant chemotherapy.
      The ratio of BRCAness of the TNBCs was approximately the same as determined in our study for patients with early-onset breast cancer (60.9% vs. 62.5%; Supplemental Table 2; available in the online version). However, the findings for the other subtypes differed from ours. Our previous study found BRCAness is an independent negative prognostic factor for RFS and OS of patients with TNBC.
      • Mori H.
      • Kubo M.
      • Nishimura R.
      • et al.
      BRCAness as a biomarker for predicting prognosis and response to anthracycline-based adjuvant chemotherapy for patients with triple-negative breast cancer.
      In the present study, multivariate analysis revealed that BRCAness was an independent negative prognostic factor when we included early-onset breast cancer.
      According to the Japanese Breast Cancer Society, the ratio of breast cancer patients with a positive FH for breast cancer in Japan was 1185/14,749 (8.0%) in 2004 and 10,080/78,897 (12.8%) in 2014 (Supplemental Figure 1; available in the online version).
      The Report of Breast Cancer Patient Registration survey by the Japanese Breast Cancer Society, no. 45, 2014.
      Furthermore, we found 116 patients (12.7%) with a positive FH for breast cancer when we investigated 801 primary breast cancer patients (regardless of subtype) who had undergone resection at our institution from January 2005 to December 2013 (Supplemental Figure 1; available in the online version). Our present analysis has revealed that 20 of the 124 patients (16.1%) had a breast cancer-specific FH. Therefore, the population of patients with early-onset breast cancer and/or TNBC might be more likely to have a positive FH for cancer than would other patients with breast cancer diagnosed at an age > 40 years or with other tumor subtypes. Certain studies have suggested that no evidence supports an association between a positive FH of breast cancer in first- and second-degree relatives and the severity of disease and breast cancer-specific mortality.
      • Melvin J.C.
      • Wulaningsih W.
      • Hana Z.
      • et al.
      Family history of breast cancer and its association with disease severity and mortality.
      • Chang E.T.
      • Milne R.L.
      • Phillips K.A.
      • et al.
      Family history of breast cancer and all-cause mortality after breast cancer diagnosis in the Breast Cancer Family Registry.
      Therefore, the clinical management should not differ according to the FH when the underlying mutation is unknown. In women aged < 35 or 40 years with a positive first-degree FH of breast or ovarian cancer, the positive FH was not associated with survival.
      • Figueiredo J.C.
      • Ennis M.
      • Knight J.A.
      • et al.
      Influence of young age at diagnosis and family history of breast or ovarian cancer on breast cancer outcomes in a population-based cohort study.
      • Eccles B.K.
      • Copson E.R.
      • Cutress R.I.
      • et al.
      Family history and outcome of young patients with breast cancer in the UK (POSH study).
      However, our present results have shown that a positive FH of breast, ovarian, pancreatic, and/or prostate cancer in first- to third-degree relatives is an independent negative prognostic factor for early-onset breast cancer and TNBC. These results might be because we focused on a limited population of early-onset and TNBC patients. However, these findings have confirmed the results reported by Slattery et al
      • Slattery M.
      • Berry T.
      • Kerber R.
      Is survival among women diagnosed with breast cancer influenced by family history of breast cancer?.
      and Wang et al.
      • Wang Y.A.
      • Jian J.W.
      • Hung C.F.
      • et al.
      Germline breast cancer susceptibility gene mutations and breast cancer outcomes.
      Moreover, we evaluated the combination of BRCAness and FH. We found no overall significant association between the presence of BRCAness and a positive FH. However, when patients were allocated into subgroups according to BRCAness and FH, the BRCAness with positive FH subgroup experienced significantly shorter survival. The patients with BRCAness but without a positive FH had a better prognosis, which was equivalent to that of patients with non-BRCAness.
      To the best of our knowledge, ours is the first study of BRCAness and FH in patients with breast cancer. The combination of BRCAness and a positive FH might represent the most robust predictive factor for prognosis for patients with early-onset breast cancer or TNBC. Although most previous studies found no convincing evidence on the prognostic effect of a positive FH, we found that the prognosis of patients with BRCAness and a positive FH was significantly worse. If we select patients with a high risk of recurrence that is associated with BRCAness and perform careful and continuous monitoring of their FH, administer appropriate treatment, and conduct surveillance, it might be possible to improve the prognosis of patients with early-onset breast cancer and TNBC.
      The present study had some limitations. First, it included only retrospectively collected cases. Second, the sample size was small because we focused on a limited population.

      Conclusion

      Our data have indicated that BRCAness tumors with a positive FH are associated with a poor prognosis for patients with early onset-breast cancer and/or TNBC. We propose therefore that BRCAness status and the FH could be used to predict patients’ prognosis.

      Clinical Practice Points

      • Early-onset breast cancer and TNBC cases are likely to include BRCA-mutated breast cancer.
      • BRCAness is defined as traits that certain sporadic cancers share with carriers of BRCA mutations.
      • A positive FH for breast cancer is a clue to the identification of hereditary breast cancer and a strong risk factor for the onset of breast cancer; however, no evidence supports an association between a positive FH and the prognosis in most Asian countries, where genetic examinations and surveillance were not available easily and inexpensively.
      • We found that BRCAness and a positive FH were independent and negative prognostic factors for patients with a high risk of BRCA mutations (ie, those with early-onset breast cancer or TNBC).
      • Furthermore, the patients with BRCAness tumors with a positive FH of cancer had the worst prognosis of the patients included in our study.
      • In the future, we could improve the prognosis of patients with early-onset breast cancer and/or TNBC if we could distinguish patients with the high risk of recurrence that is associated with BRCAness.

      Disclosure

      The authors declare that they have no competing interests.

      Acknowledgments

      The authors thank Dr Junji Kishimoto of the Center for Clinical and Translational Research at Kyushu University Hospital, Fukuoka, Japan, for his assistance with the statistical analyses of our study, Hiroshi Fujii for technical assistance, and Yasuhiro Shimoda and Arata Takahashi for performing the MLPA reactions. The authors received a Young Encouragement Award supported by the 41st Annual Meeting of the Japanese Society for Genetic Counseling, 2017. This work was supported by the Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research (grant 20591550) and JSPS KAKENHI Grant-in-Aid for JSPS Research Fellow (grant 18J20301).

      Supplemental Data

      Figure thumbnail fx1
      Supplemental Figure 1Breast Cancer Family History (BCFH) of All Patients With Breast Cancer in Japan Showing the Data Current From the Annual Aggregation of Breast Cancer Patient Registration by the Japanese Breast Cancer Society (JBCS) in 2004 and 2014 and the BCFH of All Breast Cancer Patients (Regardless of Subtype) in Our Institution From 2005 to 2013
      Supplemental Table 1Patient and Tumor Characteristics Stratified by Positive Family History
      CharacteristicFamily History Positive for CancerP Value
      Yes (n = 27)No (n = 97)
      Age at diagnosis.04
      Logistic regression analysis.
      ,
      Statistically significant difference.
       Mean44.551.6
       Range28-6725-84
      Tumor size
       T1 (≤2 cm)10 (37.0)52 (53.6).22
      Pearson's χ2 test.
       T2 (>2 but ≤ 5 cm)15 (55.6)36 (37.1)
       T3 (>5 cm)1 (3.7)8 (8.3)
       T41 (3.7)1 (1.0)
      Nodal status
       N016 (59.3)72 (74.2).30
      Pearson's χ2 test.
       N1 (1−3)7 (25.9)20 (20.6)
       N2 (4−9)3 (11.1)4 (4.1)
       N3 (≥10)1 (1.0)1 (1.0)
      Pathologic stage
       I8 (29.6)44 (45.4).33
      Pearson's χ2 test.
       II16 (59.3)45 (46.4)
       III3 (11.1)8 (8.3)
      Nuclear grade
       114 (56.0)39 (42.9).29
      Pearson's χ2 test.
       21 (4.0)13 (14.3)
       310 (40.0)39 (42.9)
      Ki-67.76
      Logistic regression analysis.
       Mean33.631.0
       Range0-831-80
      Subtype.11
      Pearson's χ2 test.
       Luminal8 (29.6)29 (29.9)
       Luminal-HER24 (14.8)3 (3.1)
       HER2-enriched0 (0)3 (3.1)
       Triple negative15 (55.6)62 (63.9)
      Data presented as mean and range or n (%).
      Abbreviation: HER2 = human epidermal growth factor receptor 2.
      a Logistic regression analysis.
      b Statistically significant difference.
      c Pearson's χ2 test.
      Supplemental Table 2Tumor Subtype for Early-onset Breast Cancer Patients Stratified by BRCAness Status
      P = .18, Pearson χ2 test.
      SubtypeBRCAness (n = 29)Non-BRCAness (n = 36)
      Luminal11 (57.9)26 (72.2)
      Luminal-HER23 (15.8)4 (11.1)
      HER2-enriched0 (0)3 (8.3)
      Triple negative5 (26.3)3 (8.3)
      Data presented as n (%).
      Abbreviation: HER2 = human epidermal growth factor receptor 2.
      a P = .18, Pearson χ2 test.
      Supplemental Table 3Tumor Subtype for Early-onset Breast Cancer Patients Stratified by Family History
      P = .09, Pearson's χ2 test.
      SubtypePositive Family History (n = 16)Negative Family History (n = 39)
      Luminal8 (50.0)29 (74.4)
      Luminal-HER24 (25.0)3 (7.7)
      HER2-enriched0 (0)3 (7.7)
      Triple negative4 (25.0)4 (10.3)
      Data presented as n (%).
      Abbreviation: HER2 = human epidermal growth factor receptor 2.
      a P = .09, Pearson's χ2 test.

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