Triple-Negative Pleomorphic Lobular Carcinoma in a Mutation Carrier: A Case of Complete Pathological Response

Introduction

Breast cancer risk is significantly higher in patients with BReast CAncer (BRCA) 1/BRCA2 mutations, with a cumulative lifetime risk estimated at 85–87% and 77–84%, respectively [1]. Attempts to identify BRCA cancer phenotypes have demonstrated certain histological patterns, particularly notable in BRCA1 mutation carriers, where the tumor often demonstrates high-grade histological features, triple hormone receptor (ER, PR, HER2) negativity, and a basal-like phenotype (CK5, CK5/6, CK14, EGFR (HER1)) [2]. Novel molecular genetic evidence has supported the luminal progenitor cell role as the cell of origin in basal-like triple-negative breast cancer (TNBC) irrespective of germline BRCA1 mutation status [3].

Invasive lobular carcinoma (ILC) is a recognized “special” histological subtype of invasive breast cancer and makes up approximately 15% of all cases with recognized patterns according to the 5th edition of the World Health Organization (WHO) Classification of Breast Tumors [2,4]. Emerging evidence suggests that there is considerable genomic heterogeneity in lobular neoplasia with tumors exhibiting either few somatic mutations and/or structural alterations, harboring highly rearranged genomes, or characterized by a hypermutator phenotype [5]. This is underlying a relatively homogeneous tumor type (ie, ER/PR-positive grade 2 ILC), which exhibits a good response to adjuvant or neoadjuvant endocrine therapy, but responds poorly to chemotherapy, with lower overall survival rates than invasive ductal carcinomas [4,5]. However, in the neoadjuvant setting, the association between complete pathological response and long-term outcomes has been found to be strongest in patients with triple-negative breast cancer [6].

Herein, we present a case report of a pleomorphic ILC with triple-negative receptor status in a patient with a germline BRCA1 c.3756_3759delGTCT p.(Ser1253Argfs*10) mutation and complete pathological response following neoadjuvant chemotherapy (NACT).

Case Report

A nulliparous 28-year-old woman with a family history of BRCA1 mutation presented to the symptomatic breast clinic with a several-week history of a left breast lump. Triple assessment was completed with ultrasound imaging confirming a 60-mm heterogeneous mass and morphologically normal axillary lymph nodes. Subsequent mammographic images demonstrated an 80-mm well-defined lobulated hyperdense mass in an otherwise adipose breast (Figure 1A, 1B).

Core biopsy established a diagnosis of high-grade malignancy consistent with a poorly differentiated TNBC (Figure 1C–1F). The neoplastic cells displayed diffuse nuclear immunoreactivity for GATA3 and aberrant p53 nuclear immunoexpression. In support of a lobular phenotype, complete loss of E-Cadherin and aberrant beta-catenin immunopositivity was documented. Proliferation activity was significantly increased based on mitotic count and Ki67 labelling index estimated at 50% (Figure 1 G–K). Given immunonegativity for Pan-CK AE1/AE3, MNF116, CAM5.2, CK7, CK20, CK5, and CK8, further immunohistochemistry work-up excluded the possibility of melanoma (SOX10), hematopoietic, and/or plasma cell neoplasm (CD45, CD138, MUM1), and/or mesothelioma (WT1, calretinin). The MDT recommended CT staging, MRI breast imaging (Figure 2A, 2B), and NACT. PET CT imaging showed no evidence of distant metastatic disease.

The patient had a good radiological response to NACT (Figure 2C, 2D) with a FEC-T carboplatin regimen with concomitant zoladex fertility preservation treatment. Post-NACT imaging showed a residual cystic mass and the patient underwent a mastectomy and sentinel lymph node biopsy with plans for a delayed latissimus dorsi reconstruction following her adjuvant radiotherapy treatment. A complete pathological response (Figure 2E, 2F) was demonstrated without any evidence of metastatic disease in 2 submitted lymph nodes.

Prior to her cancer diagnosis, the patient had been reviewed by clinical genetics as her maternal grandmother had been identified as harboring a BRCA1 pathogenic mutation in the germ-line; upon Sanger sequencing for predictive genetic testing, our patient along with her mother, brother, and sister, were found to be BRCA1 c.3756_3759delGTCT p.(Ser1253Argfs*10) mutation carriers. The patient was due to start MRI screening at age 30 as per local and national guidelines. According to the new Very High Risk Guidance in the NHS Breast Screening Programme as released in 2020, she would have had annual MRI screening starting at age 25 due an >8% breast cancer risk in the next 10 years; hence, our case report demonstrates the benefit of the updated guidance.

Discussion

Hereditary breast cancer arising in BRCA1-deficient patients is commonly diagnosed as invasive carcinoma of no special type (NST) with medullary features (ie, circumscribed border, syncytial growth pattern, and lymphocytic infiltrate) [2,7]. In accordance with previous studies [8,9], a recent case-control analysis further reinforced the notion in support of breast cancer enrichment for triple-negative tumors in BRCA1 mutation carriers [10]. This study focused on pathology of tumors associated with germline pathogenic variants in 9 Breast Cancer Susceptibility Genes (ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, RAD51D, and TP53) [10].

The genetic factors implicated in the cause of BRCA1/BRCA2 mutated breast cancer phenotypes are not fully understood. It is widely recognized that germline CDH1 mutations predispose patients to diffuse gastric cancer and almost exclusively to ILC [11], but this histological subtype appears to be under-represented in BRCA1 and TP53 mutations [12]. The CIMBA consortium reviewed the histopathology of 6893 invasive breast cancers in BRCA1/BRCA2 mutation carriers [9]. Although it is recognized that breast cancers in BRCA1 mutation carriers exhibit high-grade features and triple-negative molecular subtype, lobular cancers are more frequently associated with BRCA2 pathogenic variants (8.4% vs 2.2%) [9]. An international case-control analysis of the BRIDGES study including 42 680 breast cancer patients and 46 387 control participants found that BRCA1-deficient tumors were less likely to be lobular than ductal, but more likely to be medullary than non-medullary [10].

This theme is consistently shared across various studies with conclusions drawn that ILC according to mutational status is relevant in that it is significantly under-represented in BRCA1 mutation carriers [12–14]. Petridis et al [13] searched for germ-line CDH1, BRCA2, BRCA1, TP53, CHEK2 and PALB2 mutations in 1434 cases of sporadic ILC. In this cohort, the strongest association was noted with BRCA2, found in 7% of ILC cases under the age of 40, whereas only 1 BRAC1 frameshift deletion in exon 10 was revealed in a 38-year-old patient with bilateral ER-positive ILC and LCIS in one breast and ER-positive NST and DCIS in the other [13]. Dithci et al [14] examined 3469 breast cancers and demonstrated in their subgroup analysis of ILC and BRCA mutations that 0.58% were associated with BRCA1 and 10% with BRCA2. In contrast, van Veen et al [15] reported a higher odds ratio for BRCA1 in a cohort of 302 ILCs potentially attributed to the strong family history of breast and/or ovarian cancer in relatives rather than a true association between lobular neoplasia with BRCA1.

Triple-negative ILC is a rather rare but apparently unique aggressive breast cancer; it is estimated at 2% (74 out of 4152 ILC cases) with the following molecular subtypes based on PAM50-classifier: Luminal-A (48%), HER-2-enriched (32%), basal-like (16%) and Luminal-B (3%), in decreasing order of frequency [16]. Triple-negative ILC seems to encompass equal numbers of pleomorphic and classical variants and seems to harbor specific molecular alterations (PI3K, ERBB2, and ESRRA hotspot mutations) [17]. In this context, ErbB signaling, RAS signaling, and DNA damage response pathways are significantly enriched pathways in triple-negative ILCs along with recurrent mutations in ERBB2, ERBB3, ERBB4, PI3K, PTEN, AKT1, KRAS, and MAPK genes [16].

Further meta-analysis of ILC sequencing data from 901 ILC patients across multiple cohorts has revealed only 3 out of 901 (0.33%) patients harboring germline BRCA1 mutations; in contrast to our case, ER positivity was highlighted in all 3 cases [5]. Of note, overall survival was found to be significantly poorer for ILC cases with a higher tumor mutation burden (>5 mutations/Mb), a somatic TP53 mutation as well as for grade 3 ILC cases; such ILCs are more likely ER negative [5].

In our case, we document a triple-negative pleomorphic ILC arising in a BRCA1 mutation carrier. This case report expands the heterogeneous spectrum of TNBC and contributes to a better understanding of the molecular genetic landscape that characterizes invasive pleomorphic lobular neoplasia. However, whether this tumor is BRCA1-associated remains elusive given lack of molecular genetic evidence as the formalin-fixed paraffin-embedded (FFPE) block was consumed in its entirety for immunohistochemical purpose(s). Hence, relevant molecular testing in support of BRCAness phenotype – analysis of the second hit via somatic second mutation, somatic promoter methylation and/or loss of heterozygosity (LOH) along with determination of the Homologous Recombination DNA repair Deficiency (HRD) score and BRCA1 immunohistochemistry (IHC) – could not be utilized.

Conclusions

Herein, we report an extremely rare case of pleomorphic ILC with triple-negative receptor status arising in a BRCA1 mutation carrier. Given the low number of BRCA1-mutated ILC cases documented in the literature [5] and with approximately 1800 mutations detected in human BRCA1 [18], it is rather difficult to ascertain any potential genotype-phenotype correlations. To the best of our knowledge, this is the first report of triple-negative pleomorphic ILC in a BRCA1 mutation carrier with a complete pathological response following NACT.