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INTRODUCTION
As breast cancer is the most prevalent malignancy in women globally, several risk factors have been identified. Genetic factors are crucial in breast cancer, as roughly 5%–10% of all tumors are associated with inheritable genetic mutations [12]. The most frequent genetic mutations tied to hereditary breast cancer are the breast cancer susceptibility genes (BRCA1 and BRCA2) [34]. Women possessing BRCA1/2 mutations have a reported 40 to 70% cumulative risk of developing breast cancer throughout their lifetime [56].
Genetic counseling and BRCA testing for patients and families at high risk have seen an uptick in clinical settings [7]. For individuals who test positive for BRCA mutations, annual screening using breast MRI and mammography is recommended at an early age. Risk-reducing prophylactic mastectomy is also presented as an option [8]. Consequently, the likelihood of incidental detection of early breast cancer and precancerous lesions in these patients is on the rise [9].
A plethora of studies have concentrated on survival outcomes and pertinent prognostic factors for patients with BRCA1- or BRCA2-associated invasive ductal carcinoma (IDC). Ductal carcinoma in situ (DCIS), which is considered a precursor of IDC, is often found together with IDC on pathology. Claus et al. [10] reported BRCA1/2 prevalence rates in DCIS to be similar to those in IDC based on population studies. Nonetheless, research is scant regarding the prognostic implications of DCIS in breast cancer patients harboring BRCA1/2 mutations.
In earlier studies not centered on BRCA1/2-related breast cancer, the presence of DCIS in invasive carcinoma correlated with enhanced disease-free survival (DFS) and was deemed a positive prognostic indicator [1112]. Given that invasive tumors might originate from antecedent DCIS, malignancies with concurrent DCIS likely manifest a delay in transformation, exhibiting a more indolent course [13]. IDC-DCIS has been associated with beneficial clinical traits, such as smaller tumor dimensions, lower grade, and reduced lymph node involvement [14]. Contrarily, some investigations have unveiled findings wherein IDC-DCIS displays heightened biological aggression [15].
In this study, our objective was to ascertain whether concomitant carcinoma in situ influences long-term recurrence-free survival outcomes in BRCA1/2-associated breast cancer patients. A subgroup assessment was conducted for both BRCA1 and BRCA2 mutation carriers. Additionally, multivariable analyses were executed to pinpoint potential predictive elements for recurrence in BRCA-related breast cancer.
METHODS
Study population
We retrospectively analyzed patients who underwent curative resection for breast cancer with a final pathological diagnosis of IDC between August 2003 and January 2022 at Seoul National University Bundang Hospital. Among them, 201 patients who tested positive for BRCA1/2 mutations via genetic testing were included. Patients diagnosed solely with DCIS, those with bilateral breast cancer, stage IV cancer patients, and those lacking comprehensive histologic data were excluded. Ultimately, 157 patients were considered for analysis. Based on the presence of DCIS components on pathologic evaluation, patients were categorized into 2 groups: 121 patients had both invasive cancer and DCIS (IDC-DCIS group), while 36 patients exhibited IDC only (IDC group).
The study received approval from the Institutional Review Board (IRB) of Seoul National University Bundang Hospital (No. B-2309-852-101) and was conducted following the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines for reporting observational studies [16]. Informed consent from the study participants was waived by the IRB due to the retrospective nature of the study. The trial was registered on the Clinical Research Information Service (KCT0009513, Date of registration: 05/06/2024, http://www.cris.nih.go.kr), which is approved by the WHO International Clinical Trials Registry Platform.
Data collection and definitions
Demographic data for study participants were sourced from a review of medical records. Information pertaining to age at diagnosis, tumor size, nodal status, histologic grade of the tumor, estrogen receptor (ER) status, progesterone receptor (PR) status, human epidermal growth factor receptor-2 (HER-2) expression, surgical procedures, chemotherapy, radiotherapy, bilateral oophorectomy, family history of breast cancer, and details on recurrence were extracted from these records. “Recurrence” encompassed both locoregional and distant recurrence. Contralateral breast cancer was omitted due to the challenges in differentiating genuine recurrence from a new primary malignancy. Follow-up details were recorded up to the most recent hospital visit for each patient. The 10-year DFS was calculated, with events censored at 10 years.
Statistical analysis
All statistical evaluations were conducted using IBM SPSS Statistics ver. 28.0 (IBM Corp). Continuous variables were compared using the Student t-test, while categorical variables were assessed using the chi-square test or Fisher exact test. Survival analysis was performed using the Kaplan-Meier method and the log-rank test. Both univariate and multivariate regression analyses utilized Cox proportional hazard models. All P-values were 2-sided, and P < 0.05 was considered statistically significant.
RESULTS
A total of 157 cases were evaluated in this study. The participants included carriers of BRCA1 mutations (n = 65, 41.4%), BRCA2 mutations (n = 90, 57.3%), or both (n = 2, 1.3%). The baseline clinical characteristics of the IDC-DCIS group and IDC group are detailed in Table 1. No statistically significant difference was observed regarding age at diagnosis between the groups. However, distinct expression patterns of BRCA1/2 mutations emerged. The IDC-DCIS group exhibited more BRCA2 mutations (IDC-DCIS, 76 [62.4%] vs. IDC, 16 [44.4%]; P = 0.050), whereas the IDC group had a higher mutation rate of BRCA1 (IDC-DCIS, 46 [38.0%] vs. IDC, 21 [58.3%]; P = 0.030). In terms of adjuvant treatment, the IDC group was more frequently administered both hormone therapy (IDC-DCIS, 43 [35.5%] vs. IDC, 30 [83.3%]; P < 0.001) and chemotherapy (IDC-DCIS, 100 [82.6%] vs. IDC, 35 [97.2%]; P = 0.027).
Pathological features between the groups were also compared. There was no significant distinction in tumor size or stage. However, the IDC-DCIS group demonstrated increased expression of hormone receptors (IDC-DCIS, 69 [57.0%] vs. IDC, 5 [13.9%]; P < 0.001). Conversely, the IDC group displayed a higher histologic grade (P = 0.004).
For the entire study population, the 3-, 5-, and 10-year DFS rates were 92.0%, 87.8%, and 72.1%, respectively. Recurrence rates appeared comparable between the IDC and IDC-DCIS groups (IDC-DCIS, 43 [35.5%] vs. IDC, 12 [33.37%]; P = 0.808). The 10-year DFS difference between the 2 groups was not statistically significant (IDC-DCIS, 72.9% vs. IDC, 69.2%; P = 0.745) (Fig. 1A).
Subgroup analyses were conducted separately for BRCA1 and BRCA2 mutation carriers (Table 2). Within the BRCA1 subgroup, IDC-DCIS was linked to higher rates of hormone receptor expression (IDC-DCIS, 8 [17.4%] vs. IDC, 0; P = 0.016). Notably, the presence of a DCIS component correlated with a statistically significant improvement in 10-year DFS (IDC-DCIS, 85.5% vs. IDC, 51.0%; P = 0.024) (Fig. 1B). In the BRCA2 subgroup, IDC-DCIS also indicated high rates of hormone receptor expression (IDC-DCIS, 61 [80.3%] vs. IDC, 5 [31.2%]; P < 0.001). However, contrary to the BRCA1 subgroup, IDC-DCIS in the BRCA2 subgroup was tied to a less favorable prognosis, even though the results were not statistically significant (IDC-DCIS, 65.8% vs. IDC, 91.7%; P = 0.114) (Fig. 1C). When compared to BRCA1 IDC-DCIS, the BRCA2 IDC+DCIS group showed significantly worse DFS (P = 0.045) (Fig. 2).
Cox regression analysis was utilized to examine risk factors for recurrence (Table 3). In the univariable analysis, younger age at diagnosis was a significant predictor for recurrence (hazard ratio [HR], 2.236; P = 0.049). Patients who underwent salpingo-oophorectomy experienced a substantially reduced risk (HR, 0.106; P < 0.001). Both BRCA1 IDC (HR, 4.128; P = 0.028) and BRCA2 IDC-DCIS (HR, 3.234; P = 0.032) presented heightened risks of recurrence in contrast to BRCA1 IDC-DCIS. In the multivariable analysis, salpingo-oophorectomy was a significant prognostic factor (HR, 0.112; P < 0.001), and both BRCA1 IDC (HR, 3.818; P = 0.042) and BRCA2 IDC-DCIS (HR, 3.582; P = 0.024) persisted as significant risk factors relative to BRCA1 IDC-DCIS.
DISCUSSION
In the current study, we evaluated whether the presence of a DCIS component influences the prognosis of breast cancer patients with pathologic variants of BRCA1/2 genes. To our knowledge, this is the first study to focus specifically on the prognostic significance of DCIS in BRCA1/2-positive breast cancer. We discovered that patients with DCIS components and those with IDC alone manifested distinct expression patterns for BRCA1 and BRCA2 mutations. IDC-DCIS generally exhibited greater expression of hormone receptors and a lower histologic grade. Within BRCA1 pathological variants, IDC-DCIS correlated with more favorable survival outcomes. Conversely, in BRCA2-positive breast cancer, patients with DCIS components displayed higher recurrence rates.
Historical data indicate that BRCA-associated DCIS is more frequently detected in patients with BRCA2 mutations than with BRCA1 [1718]. Breast cancer associated with BRCA1 mutations is characterized by more aggressive attributes, including a triple-negative type and elevated histological grade, and shows transition to invasive carcinoma more rapidly [919]. This could elucidate the more abundant occurrence of DCIS in BRCA2 mutation patients. Our findings harmonize with the prevailing literature, with IDC-DCIS being more affiliated with BRCA2.
Although DCIS components are perceived as premalignant lesions in sporadic breast cancer, their role in BRCA-associated breast cancer remains under-researched. Traditionally, DCIS was less frequently found adjacent to IDC in BRCA1/2 mutants compared to sporadic breast cancer cases [20]. Yet recent findings have highlighted that DCIS is routinely identified during prophylactic mastectomy for BRCA mutation carriers [21]. Yang et al. [22] illustrated that the majority of BRCA-related tumors contained DCIS. A notable concordance rate between the phenotypes of DCIS and IDC components was observed, hinting at a possible DCIS-linked premalignant pathway. Our data corroborate this, with 121 out of 157 patients (77.1%) presenting with DCIS. This high prevalence of concurrently detected DCIS suggests that DCIS might precede invasive carcinoma even in mutation carriers.
The literature proposes that IDC cohabiting with DCIS represents a distinct biological entity relative to IDC in isolation [23]. The prognostic implications of concomitant DCIS are mixed. One analysis associated IDC-DCIS with elevated Ki-67 expression and diminished ER expression, implying a more aggressive nature [15]. Conversely, Mylonas et al. [24] observed reduced expression of HER2 and Ki-67 in IDC-DCIS, signifying a less malignant phenotype. A study from Korea, which assessed 1,751 breast cancer patients, noted that those with DCIS components exhibited higher expression of ER, PR, and HER2. Still, the grade of DCIS proved more critical than its mere presence [25]. Our results specifically address the prognostic role of DCIS in BRCA1/2-mutant breast cancer, revealing different features in the IDC-DCIS group, such as association with higher hormone receptor expression rates and lower histological grade. Despite this, when analyzing BRCA1/2-positive breast cancer patients collectively, the coexistence of DCIS and IDC did not notably alter recurrence risk. Noteworthily, the subgroup evaluation for BRCA1 and BRCA2 unveiled that IDC-DCIS correlated with improved DFS in the BRCA1 group but was indicative of poorer outcomes in the BRCA2 cohort. This implies that the prognostic value of DCIS diverges based on the type of BRCA1 and BRCA2 mutation.
Risk-reducing salpingo-oophorectomy (RRSO) is heralded as the gold standard for mitigating ovarian cancer risk in BRCA mutation carriers [26]. The effects of RRSO on breast cancer risk have been meticulously scrutinized. For those with BRCA-related breast cancer undergoing breast-conserving surgery, salpingo-oophorectomy could further diminish the threat of ipsilateral breast tumor recurrence [27]. A diminished risk of contralateral breast cancer post-RRSO in both BRCA1 and BRCA2 mutation carriers has been reported [28]. Nonetheless, recent studies have challenged these purported risk reductions [29]. Our research explored predictors for both locoregional and distant recurrence, identifying salpingo-oophorectomy as a significant determinant. Diagnosis at a younger age also emerged as a noteworthy predictor for recurrence in univariable analysis, as proven by existing literature [30]. These insights underscore the importance of risk-reduction strategies for BRCA mutation carriers, particularly in the younger cohorts at augmented risk.
This study is not without limitations. Primarily, it was a single-institution endeavor with a retrospective review of the data. The sample size for certain subgroups was confined owing to the limited number of BRCA mutation patients. Additionally, despite claims of no distinct characteristics of BRCA mutation-linked breast cancer in Western patients [9], our cohort was exclusively composed of Korean women. Future prospective, multi-center research with more extensive cohorts is imperative to validate and expand on our findings.
In summation, we discerned that DCIS, when accompanying invasive carcinoma, assumes a varied prognostic role in BRCA1 and BRCA2 mutation subcategories. BRCA1/2-positive breast cancers with DCIS components are inclined to express hormone receptors and exhibit a lesser grade compared to cases with only IDC. Recognizing oophorectomy as a pivotal predictor for diminished recurrence risk accentuates the importance of contemplating this intervention in the management of BRCA1/2 mutation carriers diagnosed with breast cancer. Furthermore, the correlation between younger age at diagnosis and an escalated recurrence risk emphasizes the necessity for tailored treatment and monitoring protocols for this patient subset.
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