Conventional View May Not Apply for All Triple-Negative Breast Cancers

Stuart J. Schnitt, MD

All triple-negative breast cancers (TNBCs) are not created equal, and clinicians should consider their inherent heterogeneity during diagnosis and treatment planning, said Stuart J. Schnitt, MD, during a presentation at the 2018 Lynn Sage Breast Cancer Symposium.

Schnitt, chief of Breast Oncologic Pathology with the Dana-Farber/Brigham and Women’s Cancer Center, reviewed the conventional view of TNBC and emphasized that the conventional view may not fit all TNBCs.

“Clinicians should view TNBC as an umbrella term rather than a specific diagnosis,” he said.

TNBC, which comprises about 15% of breast malignancies, is more common among younger women and African-American women. The disease is often associated with BRCA1 germline mutation and somatic inactivation, and cannot be managed with endocrine therapy or HER-2 targeted therapy.

When compared with other types of breast cancer, TNBC is more likely to be high grade and less likely to involve the lymph nodes, Schnitt said. Patients with TNBC face a greater risk for brain and lung metastases. They also have worse breast cancer-specific survival and overall survival rates, even after adjusting for age, stage, race, grade, and adjuvant chemotherapy.

According to Schnitt, TNBC was initially thought of as a surrogate for basal-like breast cancers identified by gene expression profiling.

“However, we’ve learned that not all TNBCs are basal-like, and not all basal-like breast cancers are triple negative,” he said. “What’s more, even TNBCs are a heterogeneous group since we have used RNA and DNA profiling to identify additional molecular subtypes.”

There are 4 such stable subtypes: luminal AR, mesenchymal, basal-like immune-suppressed, and basal-like immune-activated. According to Schnitt, the TNBC subtypes have different response rates to neoadjuvant chemotherapy. Treatments that may preferentially benefit various subtypes in clinical trials include AR antagonists, immune checkpoint inhibitors and CDK4/6 inhibitors.

Importantly, physicians now know that there are low-grade forms of TNBC, including adenoid cystic carcinoma, secretory carcinoma, acinic cell carcinoma, and low-grade metaplastic carcinoma. Low-grade metaplastic carcinoma is further divided into low-grade adenosquamous and low-grade fibromatosis-like types.

“Some are histologically low grade and have a more indolent clinical course than conventional TNBC,” Schnitt said.

The low-grade forms of TNBC cluster in basal-like or claudin-low groups by gene expression profiling, and all are relatively rare. Adenoid cystic carcinoma and secretory carcinoma are underpinned by distinctive, recurrent genetic alterations, Schnitt said.

Unfortunately, decisions regarding appropriate local and systemic therapy must be made based on limited data as most of the literature consists of small retrospective series and case reports, and data from the large national databases like SEER usually do not include pathology review, rendering them less useful in these cases.

Patients who develop adenoid cystic carcinoma, a rare form of the disease that comprises only 0.1% of all breast carcinomas, are usually in their 50s or 60s. Approximately half of these masses are located in the subareolar or central region of the breast. These carcinomas may be detected mammographically or clinically as they are often tender or painful. They show a variety of histological patterns and contain a dual cell population of epithelial cells and myoepithelial cells.

Adenoid cystic carcinomas are usually triple negative, although rare cases have been estrogen receptor—positive, said Schnitt. They also are typically CD117 positive. Genetically, a characteristic feature of this tumor type is a t(6;9)(q22-23;p23-24) translocation. MYB-NFIB fusions are also common, occurring in about 50% of cases.

“Deregulation and overexpression of MYB and its target genes is a key oncogenic event in this tumor type, regardless of origin site,” he said. Adenoid cystic carcinoma patients have an excellent prognosis, although rare cases of local recurrence and lymph node and distant metastases have been reported.

Secretory carcinoma makes up about 0.15% of all breast cancers. Formerly known as juvenile breast cancer, patients’ median age is 25, although secretory carcinoma can occur at any age. Masses are typically well circumscribed and mobile and are located in the subareolar region. These tumors are typically positive for EMA, S100, CEA, alpha lactalbumin, mammaglobin, and GATA3. They also express basal cytokeratins and EGFR.

Secretory carcinomas often feature a t(12;15)(p13;q25) balanced translocation leading to ETV6-NTRK3 fusion. Patient outcome is overall favorable, especially in children and young adults, although secretory carcinoma may be more aggressive in older patients. Recurrences up to 20 years later have been recorded.

Acinic cell carcinomas infiltrate the stroma in a haphazard, microglandular pattern. Cells have clear to finely granular to coarsely granular cytoplasm and express amylase, lysozyme, and alpha-1 anti-chymotrypsin. Patients have a favorable outlook, although these carcinomas may progress to high-grade TNBC in some cases.

Low-grade metaplastic carcinomas may arise de novo or in association with benign sclerosing lesions. These are histologically bland tumors, Schnitt said, with high rates of local recurrence. Metastases are rare, although these tumors may progress to higher grade metaplastic carcinomas.

View more from the 2018 Lynn Sage Breast Cancer Symposium