If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
To compare RS results among BRCA mutation carriers and patients with sporadic breast cancer in oestrogen receptor positive (ER+), human epidermal growth factor receptor-2 negative (HER2−) breast cancer.
Methods
A systematic review was performed in accordance with PRISMA and MOOSE guidelines. Retrospective cohort studies comparing RS in BRCA mutation carriers and cases of sporadic cancer were included. Dichotomous variables were pooled as odds ratios (ORs) and associated 95% confidence intervals (CIs) using the Mantel–Haenszel method.
Results
Five studies involving 4286 patients were included with a mean age of 60 years (range 22–85). Overall, 7.8% were BRCA mutation carriers (333/4286). The mean RS was 18.0 (range 0–71), and the mean RS in BRCA carriers was 25 (range 10–71) versus 18.4 in cases of sporadic disease (range 0–62). Patients with sporadic cancers were more likely to have RS < 18 (OR 0.27, 95% CI 0.14–0.51, P = 0.010). BRCA mutation carriers were more likely to have RS 18–30 (OR 1.74, 95% CI 1.28–2.37, P < 0.001) and RS > 30 (OR 3.71, 95% CI 2.55–5.40, P < 0.001).
Conclusion
There is an increased likelihood of high-risk RS among patients with known germline BRCA mutations when compared to patients developing sporadic ER+/HER2-early breast cancer. This study offers insight into genomic testing results within BRCA mutation carriers which may be useful in counselling patients with BRCA mutations in future practice.
]. Although BRCA1 mutations typically produce tumours with basal-like molecular properties, the penetrance of oestrogen receptor positive (ER+) disease is approximately 20–30%, with BRCA2 mutations producing ER+ cancers in 45–75% [
Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA).
Cancer Epidemiol Biomarkers Prev.2012; 21: 134-147
Breast cancer prognosis in BRCA1 and BRCA2 mutation carriers: an International Prospective Breast Cancer Family Registry population-based cohort study.
] demonstrated that patients with BRCA mutations developed increased rates of disease recurrence and mortality compared to their counterparts within the setting of ER+ disease. Highlights from such studies encourage robust systemic chemotherapy prescription for such patients possessing BRCA mutations [
], primarily due to the perceptions of increased sensitivity to chemotherapy, poorer projected clinico-oncological outcomes and an overall increased tendency to develop tumours of aggressive clinicopathological characteristics [
]. In spite of this, neither expert consensus statements nor best practice guidelines endorse such aggressive treatment strategies for BRCA mutation carriers diagnosed with early-stage ER+ disease [
The molecular era has facilitated the development of multigene panels to aid prognostication and therapeutic decision making for patients diagnosed with early-stage luminal breast cancer [
Multi-gene prognostic signatures and prediction of pathological complete response to neoadjuvant chemotherapy in ER-positive, HER2-negative breast cancer patients.
Disease recurrence and oncological outcome of patients treated surgically with curative intent for estrogen receptor positive, lymph node negative breast cancer.
Breast cancer prognosis in BRCA1 and BRCA2 mutation carriers: an International Prospective Breast Cancer Family Registry population-based cohort study.
]; however within the context of luminal A disease, there are limited data comparing the clinical utility of RS testing among BRCA mutation carriers and patients with sporadic breast cancer. Therefore, the current study aimed to compare RS results among BRCA mutation carriers and patients with sporadic breast cancer following surgical resection of their primary ER+/HER2− breast cancer. Our hypothesis was that patients possessing germline BRCA mutations would have increased RS compared to those developing sporadic breast cancer.
2. Methods
This systematic review and meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and MOOSE guidelines [
Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis of Observational Studies in Epidemiology (MOOSE) group.
]. Each author contributed to formulating the study protocol. Local institutional ethical review and approval was not required.
2.1 PICO
Using the PICO framework, the aspects the authors wished to address were:
Population: Female patients with newly diagnosed ER+ breast cancer aged 18 years or older without distant metastatic disease who underwent RS testing (Genomic Health Inc.) performed on their resected breast cancer specimen.
Intervention: Any patient in the selected group found to be a BRCA mutation carrier; this included patients possessing BRCA1 mutations, BRCA2 mutations, or BRCA variant of unknown significance (VUS).
Comparison: Any patient in the selected group who had sporadic breast cancer (i.e., are not known to be BRCA mutation carriers).
Outcomes: Primary outcomes included the following: RS genomic testing results conducted on resected breast cancer tissue.
2.2 Search strategy
An electronic search was performed of the PubMed, MEDLINE, EMBASE and Scopus databases for relevant studies. This search was performed by 2 independent reviewers (MGD and VR), using a predetermined search strategy that was designed by the senior authors (AJL and MJK). This search included the search terms: (Oncotype) and (BRCA), with ‘AND’ as a Boolean operator. Included studies were limited to the English language and were not restricted by year of publication. All duplicate studies were manually removed, before titles were screened, and studies considered appropriate had their abstracts and/or full text reviewed. Retrieved studies were reviewed to ensure that inclusion criteria were met for one primary and secondary outcome at a minimum. In cases of discrepancies of opinion a third author was asked to arbitrate (AJL). The final search was performed on the 5th March 2021.
2.3 Inclusion and exclusion criteria
Studies included were clinical studies comparing patients known to be BRCA mutation carriers (confirmed through genetic testing) and patients diagnosed with sporadic breast cancer cases who have undergone RS genomic testing on their resected cancer specimen. All studies included female patients aged 18 years or greater diagnosed with ER+ (defined in accordance with the American Society of Clinical Oncology/College of American Pathologists [ASCO/CAP] as >1% ER expression on immunohistochemical analysis) and HER2− (defined as a score of 0 or 1+ on immunohistochemical staining or HER2− following fluorescence in situ hybridisation) breast cancer on resected histopathological specimen [
American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer (unabridged version).
Human epidermal growth factor receptor 2 testing in breast cancer: American society of Clinical oncology/College of American Pathologists clinical practice guideline focused update.
]. Outcomes of interest included RS testing and clinicopathological data. Studies including patients with metastatic breast cancer were excluded. Published abstracts from conference proceedings were excluded, as were case reports, case series reporting outcomes in five patients or less and editorial articles.
2.4 Data extraction and quality assessment
The following data were extracted and collated from retrieved studies meeting inclusion criteria: (1) first author name, (2) year of publication, (3) study design, (4) country of origin, (5) number of patients, (6) number of patients with BRCA mutations, (7) number of patients with sporadic breast cancer (8) median age (and range) at diagnosis, (9) mean RS, (10) RS categorisation and (11) clinicopathological data. Risk of bias and methodology quality assessment was performed in accordance to the Newcastle–Ottawa Scale [
Descriptive statistics were used to determine associations between BRCA mutation carriers and sporadic breast cancers and RS categories. Data were expressed as dichotomous or binary outcomes, reported as odds ratios (ORs) with 95% confidence intervals (CIs) following estimation using the Mantel–Haenszel method. Either fixed or random-effects models were applied on the basis of whether significant heterogeneity (I2 > 50%) existed between studies included in the analysis. Symmetry funnel plots were used to assess publication bias. Statistical heterogeneity was determined using I2 statistics. All tests of significance were two-tailed with P < 0.050 indicating statistical significance. Descriptive statistics were performed using the Statistical Package for Social Sciences (SPSS) version 26 (International Business Machines Corporation, Armonk, NY). Meta-analysis was performed using Review Manager (RevMan), Version 5.4 (Nordic Cochrane Centre, Copenhagen, Denmark). MGD performed each statistical analyses with supervision of the senior author (MJK).
3. Results
3.1 Literature search
The initial electronic literature search retrieved 264 studies. Overall, 23 duplicate studies were manually extracted. The remaining 241 titles were screened for relevance, before 11 studies had their abstracts, and 10 manuscripts had their full texts reviewed. In total, 5 studies fulfilled our inclusion criteria and were included in quantitative and meta-analyses (Table 1, Fig. 1).
Table 1Details of included studies in this analysis.
Author
Year
Study Type
Country
N
Mean Age (Range)
BRCA (N)
BRCA 1 (N)
BRCA 2 (N)
BRCA VUS (N)
Sporadic (N)
NOS
Blanter
2020
RC
USA
723
N/R
32
5
7
18
691
7
Casasanta
2020
RC
USA
714
51
166
10
31
84
548
6
Halpern
2017
RC
Israel
1621
61 (25–85)
27
13
14
–
1594
7
Lewin
2016
RC
Israel
1078
60 (34–85)
58
20
38
–
1020
8
Shah
2016
RC
USA
150
44 (22–70)
50
19
31
–
100
7
N, number; VUS, variant of unknown significance; NOS, Newcastle–Ottawa Scale; RC, retrospective cohort; USA, United States of America; N/R, not reported.
]. Overall, 4286 patients were included in this analysis with a mean age of 60 years (range 22–85). Of these, 7.8% were BRCA mutation carriers (333/4286) while the vast majority were sporadic breast cancer patients (92.2%, 3953/4286). Table 1 demonstrates patient demographic data within BRCA and sporadic breast cancer subgroups.
The mean RS was 18.0 (range 0–71). All studies used the traditional numerical categorization of RS: This considered RS < 18 as low risk, RS 18–30 as intermediate risk and RS > 30 as high risk as validated by Paik et al. [
]. Overall, 52.6% had RS < 18 (2247/4270), 37.0% had RS 18–30 (1581/4270) and 10.4% had RS > 30 (442/4270).
In patients with BRCA mutations, the mean RS was 25 (range 10–71) versus 18.4 in those with sporadic breast cancers (range 0–62). Patients with BRCA1 mutations had a mean RS of 26.7 (range 12–61) and patients with BRCA2 mutations had a mean RS of 23.8 (range 10–71). Patients with BRCA VUS mutations had a mean RS of 25.9 (range 3–31). Table 2 illustrates RS testing results in BRCA mutation carriers and in sporadic breast cancer patients.
Overall, patients with sporadic cancers were more likely to have RS < 18 (OR 0.27, 95% CI 0.14–0.51, P = 0.010, I2 = 68%) (Fig. 2A). BRCA mutation carriers were more likely to have RS 18–30 (OR 1.74, 95% CI 1.28–2.37, P < 0.001, I2 = 0%) and RS > 30 (OR 3.71, 95% CI 2.55–5.40, P < 0.001, I2 = 0%) (Fig. 2B and C). Fig. 3 illustrates that BRCA mutation carriers are more likely to have grade III disease (OR 3.87, 95% CI 2.57–5.81, P < 0.001, I2 = 0%). Descriptive statistics correlating RS with sporadic and BRCA-associated breast cancers are illustrated in Supplementary Appendix 1.A. Forest plots for other clinicopathological data and the associated funnel plots for Fig. 2, Fig. 3 are presented in Supplementary Appendices 1.B–1.F. Descriptive statistics correlating clinicopathological data with BRCA status in breast cancer patients are outlined in Supplementary Appendix 1.G.
To our knowledge, this systematic review and meta-analysis of current evidence is the first outlining the impact of BRCA germline mutations on RS testing within the setting of early-stage ER+/HER2− breast cancer. Results of the current analysis reject the author’s null hypothesis; there was a stepwise increase in the proportion of patients with hereditary breast and ovarian cancer syndrome (HBOCS) as RS testing results increased from low, to intermediate, to high risk groups. Additionally, we observed an increase in mean RS among this cohort when compared to those with sporadic ER+/HER2− disease.
The current analysis associates BRCA mutations with increased RS in the context of patients with early-stage ER+/HER2− breast cancer. RS testing is derived from an equation which incorporates the expression of genes representing ER, progesterone receptor (PgR) and HER2/neu through reverse-transcription quantitative polymerase chain reaction products [
], where subsequent determined values for steroid hormones (i.e., ER and PgR) are negatively deducted from the RS total. At present, ASCO/CAP guidelines classify ER expression in dichotomy based on immunohistochemical results, which use ≥1% expression as the cut-off in dictating ER status [
American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer (unabridged version).
Therapy response and prognosis of patients with early breast cancer with low positivity for hormone receptors – an analysis of 2765 patients from neoadjuvant clinical trials.
], and this datum demonstrates 40% of BRCA1-related cancers to have RS > 30, compared to 10% in cases of sporadic tumours. This proves interesting finding when viewed in the context of previous studies: A recent meta-analysis of 47,000 patients highlighted that BRCA1 carriers have increased propensity of developing cancer of the triple negative breast cancer (TNBC) molecular phenotype, compared to BRCA2 carriers (OR 3.292, 95% CI 2.773–3.909) and patients with sporadic disease (OR 8.889, 95% CI 6.925–11.410) [
]. Thus, BRCA mutations are likely to be associated with high RS (given the aforementioned algorithm used to generate RS), with multiple studies demonstrating germline mutations at BRCA1 (chromosome 17q21) increasing patient susceptibility to developing ER− tumours [
]. These previous studies support the findings in the current analysis. Furthermore, dysregulation of BRCA1 is thought to inhibit ER-alpha (ER-a) transcriptional activity [
]: PgR is representative biomarker of ER-a signalling, making it somewhat unsurprising that high-risk RS is increasingly common in the setting of BRCA1 germline mutations. The data from the current analysis validate these hypotheses, with BRCA mutation carriers demonstrating increased mean RS, as well as an increased proportion of high-risk RS.
This meta-analysis correlates increased RS and tumour grade to BRCA mutation status. Although at present there is uncertainty in estimating overall prognoses for BRCA carriers [
], some may consider these results linking RS, grade and BRCA status unsurprising, as hereditary breast carcinoma has been previously associated with the development of aggressive clinicopathological features [
]. Histopathological tumour grading is a compositive scoring system which incorporates the degree of nuclear pleomorphism, mitotic indices and tubular formation within cancer cells, all of which are contributary to proliferation determined within the RS signature [
], validating their inclusion in the 21-gene signature: BRCA1 mutation carriers have the tendency to develop poorly differentiated cancers, due to higher nuclear pleomorphism, higher mitotic indices and less tubular formation, when compared to age-matched sporadic breast cancer controls (66–84% in BRCA1 versus 21–36% in sporadic tumours) [
Pathology of familial breast cancer: differences between breast cancers in carriers of BRCA1 or BRCA2 mutations and sporadic cases. Breast Cancer Linkage Consortium.
Immunohistochemical characteristics defined by tissue microarray of hereditary breast cancer not attributable to BRCA1 or BRCA2 mutations: differences from breast carcinomas arising in BRCA1 and BRCA2 mutation carriers.
]. Similarly, BRCA 2 mutations cause an increased tendency to develop high grade, with the vast majority demonstrating grade II–III disease due to similar nuclear pleomorphism and mitotic indices to sporadic tumours with less associated tubular formation (41–57% in BRCA2) [
Pathology of familial breast cancer: differences between breast cancers in carriers of BRCA1 or BRCA2 mutations and sporadic cases. Breast Cancer Linkage Consortium.
Immunohistochemical characteristics defined by tissue microarray of hereditary breast cancer not attributable to BRCA1 or BRCA2 mutations: differences from breast carcinomas arising in BRCA1 and BRCA2 mutation carriers.
]. While our results conform with the expectancies of increased tumour grade in HBOCS, the current analysis further develops the discussion to encompass increased RS testing within ER+ disease with germline BRCA mutation, as not previously demonstrated through analyses of large volume data.
In the current analysis, 10.9% of all patients with tumours with RS > 30 were diagnosed in BRCA mutation carriers (48/442). This suggests the possibility of an increased penetrance of potentially undiagnosed BRCA mutations in patients with ER+/HER2− tumours, which subsequently will be stratified to be RS > 30 following genomic testing after cancer diagnosis. Overall, the total patient cohort included in this study represent a typical distribution of expected RS for patients diagnosed with early-stage ER+ disease [
], providing a fair representation of anticipated scores for this cohort. This poses the question as to how these results may be clinically extrapolated into the population, as to ensure patients may be better served in prospective practice: Perhaps the expansion of indications for routine genetic screening of this cohort for breast cancer susceptibility may be warranted, with the aforementioned criteria (i.e., ER+/HER2− breast cancers with RS > 30) being incorporated into novel indications for genetic testing in order to capture the 10% with potentially underlying genetic mutations. Although this meta-analysis illustrates the underlying risk of patients with RS > 30 to possess a hereditary predisposition to breast cancer (i.e., BRCA1 and BRCA2 germline mutations), this is supported through recent data published by the Breast Cancer Association Consortium highlighting the relevance genetic mutations in the quantification of breast cancer risk [
This meta-analysis suffers from a number of limitations: All data were collated from retrospective cohort studies indicating moderate levels of evidence. The authors acknowledge that patients harbouring BRCA1 mutations typically display the TNBC phenotype, limiting the clinical utility of this datum for a share of BRCA carriers. Furthermore, the current analysis only included 333 patients with BRCA mutations (7.8%), albeit proportional and consistent with previously published rates of BRCA mutations among breast cancer diagnoses [
First results from a phase III randomized clinical trial of standard adjuvant endocrine therapy (ET) +/- chemotherapy (CT) in patients (pts) with 1-3 positive nodes, hormone receptor-positive (HR+) and HER2-negative (HER2-) breast cancer (BC) with recurrence score (RS) < 25: SWOG S1007 (RxPonder).
], limiting the conclusions which may be drawn from this analysis. In spite of these limitations, the authors wish to reiterate that this analysis is the largest providing real-world data in relation to genomic testing within the context of ER+ disease in BRCA mutations carriers.
In conclusion, this systematic review and meta-analysis of current evidence illustrates increased RS among patients with known germline BRCA mutations when compared to patients developing sporadic ER+/HER2− early breast cancer. The current study offers insights with respect to anticipated genomic testing results for patients with BRCA germline mutations and subsequently develop early-stage ER+ breast cancer, which highlights the potential to expand genetic testing indications to encompass those deemed high risk following genomic substratification.
Author contribution statement
MGD generated the initial concept, performed review of the literature and data extraction from relevant studies, performed relevant statistical analyses and prepared and redrafted the manuscript for submission to journal.
VR performed review of the literature and data extraction from relevant studies, prepared and revised redrafts of manuscript and reviewed the final draft prior to submission.
AJL provided supervision of other authors during the early phases of the study, provided corrections to drafts of manuscript and reviewed final draft prior to submission.
MJK generated the initial concept, provided supervision of other authors during the early phases of the study, arbitrated discrepancies in opinion regarding study relevance and inclusion, provided corrections to drafts of manuscript and reviewed final draft prior to submission.
Funding
MGD received stipend funding from the National Breast Cancer Research Institute, Ireland. VR received stipend funding from Precision Oncology Ireland, which is part-funded by the Science Foundation Ireland Strategic Partnership Programme, under grant number 18/SPP/3522.
Conflict of interest statement
None declared.
Appendix ASupplementary data
The following is the Supplementary data to this article:
Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA).
Cancer Epidemiol Biomarkers Prev.2012; 21: 134-147
Breast cancer prognosis in BRCA1 and BRCA2 mutation carriers: an International Prospective Breast Cancer Family Registry population-based cohort study.
Multi-gene prognostic signatures and prediction of pathological complete response to neoadjuvant chemotherapy in ER-positive, HER2-negative breast cancer patients.
Disease recurrence and oncological outcome of patients treated surgically with curative intent for estrogen receptor positive, lymph node negative breast cancer.
Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis of Observational Studies in Epidemiology (MOOSE) group.
American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer (unabridged version).
Human epidermal growth factor receptor 2 testing in breast cancer: American society of Clinical oncology/College of American Pathologists clinical practice guideline focused update.
Therapy response and prognosis of patients with early breast cancer with low positivity for hormone receptors – an analysis of 2765 patients from neoadjuvant clinical trials.
Pathology of familial breast cancer: differences between breast cancers in carriers of BRCA1 or BRCA2 mutations and sporadic cases. Breast Cancer Linkage Consortium.
Immunohistochemical characteristics defined by tissue microarray of hereditary breast cancer not attributable to BRCA1 or BRCA2 mutations: differences from breast carcinomas arising in BRCA1 and BRCA2 mutation carriers.
First results from a phase III randomized clinical trial of standard adjuvant endocrine therapy (ET) +/- chemotherapy (CT) in patients (pts) with 1-3 positive nodes, hormone receptor-positive (HR+) and HER2-negative (HER2-) breast cancer (BC) with recurrence score (RS) < 25: SWOG S1007 (RxPonder).
00408-1&id=gr1.jpg){kind=link}
00408-1&id=gr2.jpg){kind=link}
00408-1&id=gr3.jpg){kind=link}