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Relationship Between Hereditary Cancer Syndromes and Oncotype DX Recurrence Score

Published:August 21, 2019DOI:https://doi.org/10.1016/j.clbc.2019.07.004

      Abstract

      Background

      Oncotype DX (ODX) is a genomic assay of tumor tissue that is utilized to predict the likelihood of recurrence and benefit of chemotherapy in breast cancer patients. Five to 10% of breast cancers are hereditary, and hereditary syndromes may not be uncovered through family history alone. We hypothesized that high ODX recurrence score (RS) may signal a potential hereditary cancer risk.

      Patients and Methods

      We performed a retrospective analysis of data from hormone receptor–positive breast cancer patients who had undergone ODX and germline genetic testing. The chi-square test and Fisher exact test were used to examine univariable association between RS and germline mutation status. Multivariable logistic regression was utilized to examine if there was an association of RS with germline mutation status.

      Results

      In univariable analysis, the association of RS with germline mutation status was significant (P < .0001). In the multivariable logistic regression model predicting germline mutation status, RS level remained significantly associated with germline mutation, in particular BRCA1 or BRCA2. The mean RS for those with non-BRCA1/2 germline mutations versus those without germline mutations was not significant (P = .38).

      Conclusion

      High RS is associated with germline mutation status. Breast cancer patients with high RS are more likely to harbor a mutation in the BRCA1 or BRCA2 genes. If confirmed prospectively, oncologists may consider referring patients with high RS for genetic risk assessment and counseling to inform management plans, as well as counseling of family members.

      Keywords

      Introduction

      Approximately 5% to 10% of breast cancers are hereditary.
      • Valencia O.M.
      • Samuel S.E.
      • Viscusi R.K.
      • Riall T.S.
      • Neumayer L.A.
      • Aziz H.
      The role of genetic testing in patients with breast cancer: a review.
      • Foulkes W.D.
      Inherited susceptibility to common cancers.
      Studies report that between 30% and 50% of patients with hereditary breast cancer are positive for a mutation in either BRCA1 or BRCA2.
      • Valencia O.M.
      • Samuel S.E.
      • Viscusi R.K.
      • Riall T.S.
      • Neumayer L.A.
      • Aziz H.
      The role of genetic testing in patients with breast cancer: a review.
      • Arun B.
      • Bayraktar S.
      • Liu D.D.
      • et al.
      Response to neoadjuvant systemic therapy for breast cancer in BRCA mutation carriers and noncarriers: a single-institution experience.
      Additionally, up to 11% of patients who test negative for BRCA mutations test positive for mutations in other genes that confer an increased risk for breast cancer, such as CHEK2, PALB2, ATM, CDH, NBN, NF1, PTEN, STK11, and TP53.
      • Coppa A.
      • Nicolussi A.
      • D’Inzeo S.
      • et al.
      Optimizing the identification of risk-relevant mutations by multigene panel testing in selected hereditary breast/ovarian cancer families.
      • Economopoulou P.
      • Dimitriadis G.
      • Psyrri A.
      Beyond BRCA: new hereditary breast cancer susceptibility genes.
      • LaDuca H.
      • Stuenkel A.J.
      • Dolinsky J.S.
      • et al.
      Utilization of multigene panels in hereditary cancer predisposition testing: analysis of more than 2,000 patients.
      Therefore, in patients with a history indicating a potential hereditary cancer syndrome, multigene panel testing is usually considered. The National Comprehensive Cancer Network (NCCN) criteria for referral for genetic risk evaluation focus primarily on personal and/or family medical history of breast and/or ovarian cancer. A population study of 1001 patients with breast cancer who underwent an 80-gene panel found that rate of pathologic/likely pathologic variants was similar among those who did and did not meet NCCN guidelines for genetic testing.
      • Beitsch P.D.
      • Whitworth P.W.
      • Hughes K.
      • et al.
      Underdiagnosis of hereditary breast cancer: are genetic testing guidelines a tool or an obstacle?.
      These findings illustrate the need for additional clinical indicators for genetic risk evaluation.
      In addition to family history of breast cancer, some clinicopathologic features such as triple-negative breast cancer and high-grade serous epithelial ovarian cancer have been established to be predictors of hereditary breast and ovarian cancer.
      National Comprehensive Cancer Network
      NCCN clinical practice guidelines in oncology: genetic/familial high-risk assessment: breast and ovarian, version 2.2019.
      One potential clinical indicator, not yet completely described and validated in hereditary cancer patients, is Oncotype DX (ODX). ODX is a genomic assay of breast tumor tissue that utilizes a 21-gene expression profile to generate a recurrence score (RS). The RS is used to stratify early-stage hormone receptor–positive breast tumors into those with disease likely to respond to adjuvant cytotoxic chemotherapy. On the basis of existing cut points established by Genomic Health at the time of the study, RS was categorized into 3 risk groups: low (0-17), intermediate (18-30), and high (≥ 31).
      • Paik S.
      • Shak S.
      • Tang G.
      • et al.
      A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer.
      • Paik S.
      • Tang G.
      • Shak S.
      • et al.
      Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor positive breast cancer.
      Those with a high RS have a significant reduction in rates of distant recurrence when treated with sequential chemotherapy and endocrine therapy; those with low RS show no significant difference in rates of distant recurrence when treated with endocrine therapy only versus endocrine therapy and chemotherapy.
      • McVeigh T.P.
      • Kerin M.J.
      Clinical use of the Oncotype DX genomic test to guide treatment decisions for patients with invasive breast cancer.
      • Mamounas E.P.
      • Tang G.
      • Fisher B.
      • et al.
      Association between the 21-gene recurrence score assay and risk of locoregional recurrence in node-negative, estrogen receptor–positive breast cancer: results from NSABP B-14 and NSABP B-20.
      • Habel L.A.
      • Shak S.
      • Jacobs M.K.
      • et al.
      A population-based study of tumor gene expression and risk of breast cancer death among lymph node-negative patients.
      • Sparano J.A.
      • Paik S.
      Development of the 21-gene assay and its application in clinical practice and clinical trials.
      • Sparano J.A.
      • Gray R.J.
      • Makower D.F.
      • et al.
      Prospective validation of a 21-gene expression assay in breast cancer.
      • Dowsett M.
      • Cuzick J.
      • Wale C.
      • et al.
      Prediction of risk of distant recurrence using the 21-gene recurrence score in node-negative and node-positive postmenopausal patients with breast cancer treated with anastrozole or tamoxifen: a TransATAC study.
      • Albain K.S.
      • Barlow W.E.
      • Shak S.
      • et al.
      Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal women with node-positive, oestrogen-receptor–positive breast cancer on chemotherapy: a retrospective analysis of a randomised trial.
      ODX has been validated for prognosis and prediction of chemotherapy benefit in sporadic breast cancers both retrospectively and prospectively, most recently in the TAILORx study.
      • Sparano J.A.
      • Gray R.J.
      • Makower D.F.
      • et al.
      Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer.
      This study found that adjuvant endocrine therapy and chemoendocrine therapy had similar efficacy in hormone receptor–positive, HER2-negative breast cancer in patients with a midrange ODX RS of 11 to 25.
      • Sparano J.A.
      • Gray R.J.
      • Makower D.F.
      • et al.
      Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer.
      However, its predictive value has not yet been described in patients with hereditary cancer syndromes.
      Studies have shown that patients with BRCA-associated breast cancers may have enhanced sensitivity to cytotoxic chemotherapy.
      • Narod S.A.
      • Metcalfe K.
      • Lynch H.T.
      • et al.
      Should all BRCA1 mutation carriers with stage I breast cancer receive chemotherapy?.
      • Goodwin P.J.
      • Phillips K.A.
      • West D.W.
      • et al.
      Breast cancer prognosis in BRCA1 and BRCA2 mutation carriers: an International Prospective Breast Cancer Family Registry population-based cohort study.
      • Robson M.E.
      • Chappuis P.O.
      • Satagopan J.
      • et al.
      A combined analysis of outcome following breast cancer: differences in survival based on BRCA1/BRCA2 mutation status and administration of adjuvant treatment.
      • Halpern N.
      • Sonnenblick A.
      • Uziely B.
      • et al.
      Oncotype DX recurrence score among BRCA1/2 germline mutation carriers with hormone receptors positive breast cancer.
      Although BRCA-associated tumors may have more aggressive features than sporadic breast cancers as a whole, more recent data suggest individuals with BRCA-associated breast cancers tend to have similar outcomes to those with sporadic cancers.
      • Narod S.A.
      • Metcalfe K.
      • Lynch H.T.
      • et al.
      Should all BRCA1 mutation carriers with stage I breast cancer receive chemotherapy?.
      • Copson E.R.
      • Maishman T.C.
      • Tapper W.J.
      • et al.
      Germline BRCA mutation and outcome in young-onset breast cancer (POSH): a prospective cohort study.
      • Xie Y.
      • Gou Q.
      • Wang Q.
      • Zhong X.
      • Zheng H.
      The role of BRCA status on prognosis in patients with triple-negative breast cancer.
      • Lakhani S.R.
      • Van De Vijver M.J.
      • Jacquemier J.
      • et al.
      The pathology of familial breast cancer: predictive value of immunohistochemical markers estrogen receptor, progesterone receptor, HER-2, and p53 in patients with mutations in BRCA1 and BRCA2.
      Additional studies of BRCA carriers have illustrated that they have a higher median RS, more high RS disease, more intermediate RS disease, and less low RS disease compared to sporadic breast cancer cases.
      • Halpern N.
      • Sonnenblick A.
      • Uziely B.
      • et al.
      Oncotype DX recurrence score among BRCA1/2 germline mutation carriers with hormone receptors positive breast cancer.
      • Shah S.A.
      • Patil S.
      • Dickler M.N.
      • et al.
      Twenty-one-gene recurrence score assay in BRCA-associated versus sporadic breast cancers: differences based on germline mutation status.
      • Lewin R.
      • Sulkes A.
      • Shochat T.
      • et al.
      Oncotype-DX recurrence score distribution in breast cancer patients with BRCA1/2 mutations.
      Although data exist describing the associations between RS with pathogenic mutation status, there is no description of the use of ODX as an independent predictor of germline mutations in patients with undiagnosed hereditary cancer syndromes. Additionally, there are no other studies describing the association of ODX with hereditary mutations other than BRCA1 and BRCA2.
      We hypothesized that a high RS may harbor a signal of potential hereditary risk. This analysis aimed to identify whether patients with a high RS were more likely to have germline mutations than patients with low RS. Additionally, we aimed to determine whether high RS was associated with harboring a hereditary genetic mutation.

      Patients and Methods

      After receipt of approval from the local institutional review board, we performed a retrospective analysis with an exemption for informed consent.

       Sample Selection

      Our study included individuals with a personal history of breast cancer who received treatment at participating research facilities between January 2008 and April 2017, and who had a history of hormone receptor–positive breast cancer, ODX testing, and germline genetic testing. ODX and germline genetic testing were performed on the basis of clinical criteria.

       Measures

      ODX RS was recorded along with the type of genetic testing and the genetic testing results. Additional patient and tumor variable data were collected, including gender, ethnicity, age at diagnosis, tumor, node, metastasis classification system (TNM) stage, histologic subtype, histologic grade, HER2 status, multifocality, and tumor size. Patients considered estrogen receptor positive included estrogen receptor ranging from 22% to 100%, and those considered progesterone receptor positive had progesterone receptor ranging from 10% to 100% on fluorescence in-situ hybridization testing.

       Coding of Germline Mutations

      Because the data collection period goes back to 2008 and multigene panel testing only became widely available in 2013, genes that were tested and number of genes tested varied across subjects. In order to create a single binary germline mutation variable for the primary analysis, those patients with deleterious mutations in any known hereditary cancer gene were considered positive for a mutation. Individuals who tested negative for all genetic mutations included in their genetic test were considered negative. Those who had variant of uncertain significance (VUS) were coded as having no germline mutation in the primary analysis. In sensitivity analyses, these were coded either as a separate (third) category or excluded. In secondary analyses, we examined additional ways to code germline mutations. First, we examined the association of RS with the individual genes that were most commonly tested, using BRCA1 and BRCA2 as individual variables. Each of these was coded as positive for a mutation, normal, or not tested for each subject. We also created an ‘either BRCA1 or BRCA2’ variable, coded positive if either of these was present and negative if both were absent. This allowed us to examine whether RS was associated with mutations in these genes using only those subjects for whom these genes were tested. In order to examine whether the entire germline mutation association with RS was explained by BRCA1 or BRCA2 mutations, we also created a binary variable indicating positive germline mutations other than BRCA1 or BRCA2. For this variable, those who were positive for BRCA1 or BRCA2 and those only tested for BRCA1 or BRCA2 were coded as not tested.

       Coding of Oncotype RS

      We used both the continuous RS score and an ordinal coding of this variable in different analyses. RS was categorized as low (0-17), intermediate (18-30), and high (≥ 31).
      • Paik S.
      • Tang G.
      • Shak S.
      • et al.
      Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor positive breast cancer.
      • Desmond A.
      • Kurian A.W.
      • Gabree M.
      • et al.
      Clinical actionability of multigene panel testing for hereditary breast and ovarian cancer risk assessment.

       Data Analysis

      Continuous variable distributions were examined for outliers and nonnormality, and data were transformed if necessary. For each germline mutation variable, we performed a chi-square test or Fisher exact test comparing RS level (low, intermediate, high) for those with a mutation versus without a mutation, and we used a t test to compare mean RS scores for those with and without a mutation, or analysis of variance when VUS was included as a third category. Univariable associations between germline mutation variables and ODX RS variables were examined first. We also examined patient and tumor variables associated with RS in order to determine which of these other patient or tumor variables might be acting as confounders in the association of ODX RS with germline mutation. We then used multivariable logistic regression to examine the independent association of RS with germline mutation status, controlling for relevant patient or tumor variables. Covariates were those that had any association (P < .10) with RS.
      SAS 9.3 (SAS Institute, Cary, NC) was used for data analysis, with P < .05 considered statistically significant.

      Results

      There were 703 patients from 3 cancer centers in the sample. Mean age at diagnosis was 51 ± 11, 95% were female, and 5% were Asian, 14% black, 52% white, and 29% of unknown race (Table 1). Of all patients in the study, 548 were negative for germline mutations (78%), 71 were positive for a germline mutation (10%), and 84 had a VUS detected (12%). Mean RS was 17.8 ± 9.5 in the full sample (range, 0-66). There were 401 patients with disease categorized as low RS (57%), 231 as intermediate RS (33%), and 71 as high RS (10%) (Table 2). RS by germline mutation is shown in Table 3.
      Table 1Patient Characteristics by Oncotype DX RS Level
      CharacteristicRS LevelP
      Low (N = 401)Intermediate (N = 231)High (N = 71)
      Age at diagnosis (years), mean ± SD51.8 ± 10.551.0 ± 10.650.1 ± 11.6.40
      Female sex381 (95)221 (96)65 (92).72
      Race.044
       Asian28 (7)8 (3)2 (3)
       Black48 (12)37 (16)13 (18)
       White217 (54)120 (52)28 (39)
       Unknown108 (27)66 (29)28 (39)
      Histologic Grade<.0001
       1125 (33)33 (15)5 (8)
       2218 (58)147 (69)21 (33)
       331 (8)33 (15)37 (59)
      TNM Stage.054
       T1313 (78)170 (74)42 (59)
       T258 (14)38 (16)21 (30)
       T34 (1)3 (1)0
       T42 (0.5)1 (0.4)0
       Unknown24 (6)19 (8)8 (11)
      Data are presented as n (%) unless otherwise indicated.
      Abbreviations: RS = recurrence score; SD = standard deviation; TNM = tumor, node, metastasis classification system.
      Table 2Sample Characteristics
      CharacteristicValue
      Sample size703
      Oncotype DX RS17.8 ± 9.5
      Mutation Status
       Noncarriers78%
       VUS12%
       Mutation carriers10%
      RS
       Low57%
       Intermediate33%
       High10%
      Abbreviations: RS = recurrence score; VUS = variant of uncertain significance.
      Table 3Oncotype DX RS by Germline Mutation
      MutationLow RSIntermediate RSHigh RS
      BRCA1145
      BRCA28167
      CHEK2323
      BRIP1121
      ATM120
      PALB2230
      TP53100
      MSH6211
      MLH1010
      MRE11A001
      MUTYH300
      APC010
      NBN300
      Total253220
      Abbreviation: RS = recurrence score.
      In univariable analysis, the association of RS with germline mutation status was significant (P < .0001). The percentages of patients with germline mutations detected in low, intermediate, and high RS categories were 6%, 13%, and 24%, respectively (Figure 1). When patients with VUS were included as a separate group in the analysis, rather than being coded as negative for mutations, this relationship remained significant (P < .0001). It also remained significant with VUS excluded (P < .0001). Mean RS was significantly different between patients with no germline mutations (17.2 ± 9.0, 95% confidence interval [CI], 16.5-17.9) versus those with germline mutations (23.1 ± 11.9; 95% CI, 20.3-25.9; P = .0001). When patients with VUS were treated as a separate category, this association remained significant (P < .00001), with the means for both the negative mutation group (17.1 ± 9.0; 95% CI, 16.3-17.9) and VUS (17.7 ± 9.2; 95% CI, 15.7-19.7) both significantly below the mean of a patient’s testing positive for a germline genetic mutation.
      Figure thumbnail gr1
      Figure 1Germline Mutation Status by RS Score. Percentage of Patients With and Without Germline Mutation in Low, Intermediate, and High RS Category (P < .0001)
      Abbreviation: RS = recurrence score.
      Patient variables associated with RS level included race (P = .044), histologic grade (P < .0001), and TNM stage (only at a trend level of significance, P = .054) (Table 1). Patients with high RS were less likely to be white than those with low RS, and had higher histologic grade and higher T variable of TNM stage.
      In the univariable analysis of the individual BRCA1 and BRCA2 mutations, both gene mutations were found to be significantly associated with higher RS scores (Table 4). The percentages of patients with germline BRCA1 mutations were 0.3%, 1.8%, and 7.1%, for low, intermediate, and high RS groups, respectively. The percentages of patients with BRCA2 mutations were 2.2%, 6.6%, and 10.0% for low, intermediate, and high RS. The rate of mutations appears to increase in a graded fashion along with RS level for both BRCA1 and BRCA2 mutation carriers (P = .0004 for BRCA1, P = .0024 for BRCA2, and P < .0001 for either BRCA1 or BRCA2). Mean RS was significantly higher for those with either BRCA1 or BRCA2 mutations versus patients without either of these mutations (17.3 ± 9.0 and 26.3 ± 12.8; P < .0001) (Table 5).
      Table 4BRCA1/2 Genotype by Oncotype DX RS Level
      GenotypeLowIntermediateHighP
      BRCA PositiveN = 401N = 229N = 70
      BRCA1 positive1 (0.3)4 (1.8)5 (7.1).0004
      BRCA2 positive9 (2.2)15 (6.6)7 (10.0).0024
       Either BRCA1 or BRCA2 positive10 (2.5)19 (8.2)12 (16.9)<.0001
      Non-BRCA positiveN = 136N = 84N = 25
      17 (12.5)10 (11.9)6 (24).38
      Data are presented as number positive (column %).
      Abbreviation: RS = recurrence score.
      Table 5Mean Oncotype DX RS by BRCA Genotype
      GenotypeNegativePositiveP
      BRCA117.6 ± 9.232.1 ± 14.4.011
      BRCA217.5 ± 9.224.4 ± 11.9.0031
      Either BRCA1 or BRCA217.3 ± 9.026.3 ± 12.8<.0001
      Abbreviation: RS = recurrence score.
      The sample was also analyzed for the proportion of cases with non-BRCA germline mutations for those with low, intermediate, and high RS. These proportions were 12.5%, 11.9%, and 24%, respectively (P = .38) (Table 4). The mean RS for those with non-BRCA1/2 germline mutations versus those who tested negative for germline genetic mutations was not significant (18.8 ± 8.9 vs. 17.3 ± 8.9; P = .38).
      In the adjusted analysis with RS level predicting germline mutation using multivariable logistic regression, adjusting for race, histologic grade, and T variable of TNM stage, RS level remained significantly associated with germline mutation (adjusted odds ratio [OR] for high vs. low RS = 3.99 [95% CI 1.78-8.92], P = .0007; adjusted OR for intermediate vs. low RS = 1.97 [1.08-3.57], P = .026). Excluding subjects with VUS did not change these findings (adjusted OR for high RS = 4.46 [1.96-10.17], P = .0004; adjusted OR for intermediate RS = 2.09 [1.14-3.83], P = .017).
      In the logistic regression model for predicting a germline mutation in either BRCA1 or BRCA2, adjusting for race, histologic grade, and T variable of TNM stage, RS level remained significantly associated with germline BRCA1 or BRCA2 mutation (adjusted OR for high vs. low RS = 7.56 [95% confidence interval, 2.52-22.67], P = .0003; adjusted OR for intermediate vs. low RS = 3.69 [1.54-8.85], P = .0034).

      Discussion

      In this study, we showed a statistically significant stepwise increase in proportion of patients with hereditary cancer mutations as ODX increased from low to intermediate to high RS. Patients who tested positive for germline mutations in genes associated with hereditary cancers were also found to have a significantly higher mean RS than those who tested negative for genetic mutations. After adjusting for race, histologic grade, and TNM stage with multivariate analysis, high RS remained associated with harboring a germline mutation. These findings were driven by patients with BRCA1 and BRCA2 mutations because the proportion of non-BRCA mutation carriers in each RS group was not statistically different.
      Our study supported findings of previous studies: patients with BRCA mutations were more likely than non-BRCA mutation carriers to have high and intermediate RS disease.
      • Lakhani S.R.
      • Van De Vijver M.J.
      • Jacquemier J.
      • et al.
      The pathology of familial breast cancer: predictive value of immunohistochemical markers estrogen receptor, progesterone receptor, HER-2, and p53 in patients with mutations in BRCA1 and BRCA2.
      Mean RS was also significantly higher in patients with germline mutations.
      • Shah S.A.
      • Patil S.
      • Dickler M.N.
      • et al.
      Twenty-one-gene recurrence score assay in BRCA-associated versus sporadic breast cancers: differences based on germline mutation status.
      These findings are consistent with reports that tumors found in patients with hereditary cancer syndromes have increased sensitivity to cytotoxic chemotherapy, as patients with high ODX RS have shown a decreased risk of recurrence benefit with adjuvant chemotherapy in early-stage hormone receptor–positive breast cancers.
      • Lewin R.
      • Sulkes A.
      • Shochat T.
      • et al.
      Oncotype-DX recurrence score distribution in breast cancer patients with BRCA1/2 mutations.
      One additional study demonstrated BRCA mutation status to be an independent predictor of RS.
      • Lewin R.
      • Sulkes A.
      • Shochat T.
      • et al.
      Oncotype-DX recurrence score distribution in breast cancer patients with BRCA1/2 mutations.
      We were able to replicate these results and expand on them by including non-BRCA mutation carriers in our analysis.
      Our study uniquely included patients with mutations in hereditary cancer genes other than BRCA1 and BRCA2. The relationship between non-BRCA hereditary cancers and ODX score has not yet been studied to date. Our study demonstrated that the relationship between germline mutation and ODX score is primarily driven by BRCA1 and BRCA2 mutation carriers.
      As this data suggests that high RS may serve as a predictor for germline mutation status, patients with high RS are more likely to harbor hereditary cancer syndromes, particularly those associated with BRCA1 and BRCA2 mutations. This has potential clinical significance: breast tumors with high oncotype RS may serve as another clinical indictor for patient referral to genetic testing services if confirmed in prospective studies. The results of such genetic testing has the potential to significantly affect the management of each individual patient and the genetic counseling of at-risk family members.
      This study has a number of limitations, including the small sample size of the subpopulation of non-BRCA mutation carriers. This study retrospectively looked at data from 2008 to 2017, and multigene panel testing only became widely available in 2013.
      • Desmond A.
      • Kurian A.W.
      • Gabree M.
      • et al.
      Clinical actionability of multigene panel testing for hereditary breast and ovarian cancer risk assessment.
      Therefore, many of the patients in our study who received genetic testing before 2013 only received BRCA mutation testing. This limited the number of patients in our study who utilized multigene panel testing. Furthermore, patients in our study utilized a wide variety of multigene panel tests, analyzing between 1 and 49 different genes known to be associated with hereditary cancer syndromes. Although our study analyzed BRCA1 and BRCA2 testing individually, the type of multigene panel testing and the number of genes analyzed for each individual patient varied. Therefore, the number of patients included in the non-BRCA analysis as negative for a mutation could be an underestimation. Additionally, the overall frequency of non-BRCA1/2 mutations in patients with breast cancer is lower than the frequency of BRCA1 and BRCA2 mutations.
      • Tung N.
      • Battelli C.
      • Allen B.
      • et al.
      Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel.
      As genetic testing technology has improved and become more accessible, more sophisticated genetic testing has become standard. For instance, the BRACAnalysis Rearrangement Test only became standard in 2012, and repeat testing is often recommended for patients who had sequence analysis testing alone. Patients in our population who underwent testing before this became standard may not have had complete testing and therefore may have had a false-negative genetic test result. Additionally, because this was a retrospective review, our sample was a population that met the NCCN guidelines for genetic counseling and screening. Therefore, our sample could be considered a population enriched with those with risk factors for hereditary mutations—although only 10% were positive for hereditary mutations, which is within the reported frequency of cancers caused by hereditary mutations.
      In summary, our study showed that high RS is associated with germline mutation status, and breast cancer patients with high RS are more likely to harbor a mutation in the BRCA1 or BRCA2 genes. Therefore, oncologists might consider referring patients with high RS for genetic risk assessment and counseling if further prospective data confirm our findings. Uncovering a hereditary mutation makes an important impact on clinical care of patients and their families through informing cancer treatment plans and the need for genetic risk assessment of family members.

       Clinical Practice Points

      • In univariable analysis, the association of RS with germline mutation status was significant (P < .0001). As RS numerically increased, the percentage of mutation carriers in each RS category increased.
      • Patients who tested positive for germline mutations in genes associated with hereditary cancers were found to have a significantly higher mean RS than those who tested negative for genetic mutations.
      • Patients with a high RS were more likely to harbor hereditary cancer syndromes. This was driven by patients with BRCA1 and BRCA2 mutations.
      • RS is associated with germline mutation status.
      • RS may serve as a new clinical indicator to trigger genetic counseling and testing in breast cancer patients with further confirmatory data.
      • If prospective data support our findings, clinicians may consider testing patients with high RS for germline mutations to help guide appropriate therapy and other family members at risk.

      Disclosure

      E.S. is a consultant for Color Genomics. The other authors have stated that they have no conflict of interest.

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