Rare subtypes of triple negative breast cancer: Current understanding and future directions

Abstract

Rare subtypes of triple-negative breast cancers (TNBC) are a heterogenous group of tumors, comprising 5–10% of all TNBCs. Despite accounting for an absolute number of cases in aggregate approaching that of other less common, but well studied solid tumors, rare subtypes of triple-negative disease remain understudied. Low prevalence, diagnostic challenges and overlapping diagnoses have hindered consistent categorization of these breast cancers. Here we review epidemiology, histology and clinical and molecular characteristics of metaplastic, triple-negative lobular, apocrine, adenoid cystic, secretory and high-grade neuroendocrine TNBCs. Medullary pattern invasive ductal carcinoma no special type, which until recently was a considered a distinct subtype, is also discussed. With this background, we review how applying biological principals often applied to study TNBC no special type could improve our understanding of rare TNBCs. These could include the utilization of targeted molecular approaches or disease agnostic tools such as tumor mutational burden or germline mutation-directed treatments. Burgeoning data also suggest that pathologic response to neoadjuvant therapy and circulating tumor DNA have value in understanding rare subtypes of TNBC. Finally, we discuss a framework for advancing disease-specific knowledge in this space. While the conduct of randomized trials in rare TNBC subtypes has been challenging, re-envisioning trial design and technologic tools may offer new opportunities. These include embedding rare TNBC subtypes in umbrella studies of rare tumors, retrospective review of contemporary trials, prospective identification of patients with rare TNBC subtypes entering on clinical trials and querying big data for outcomes of patients with rare breast tumors.

Metaplastic breast cancer and BRCA1: first strong evidence of a link

“…Metaplastic breast cancers are a heterogenous group of invasive breast cancers which share differentiation toward squamous or mesenchymal-appearing elements [ 2 ]. The reported incidence of metaplastic breast cancer can vary from approximately 0.2 to 1.0% of breast cancers depending on their definition [ 3 , 4 ] and have an incidence rate of 0.6–1.0 per 100,000 women per year in the USA[ 2 ] inferring a lifetime risk of less than 1 in 1000. Assessment by intrinsic subtypes of 28 metaplastic breast tumours found the majority were claudin-low or basal-like intrinsic subtypes [ 5 ] with most being triple negative [ 2 ].…”

“…The reported incidence of metaplastic breast cancer can vary from approximately 0.2 to 1.0% of breast cancers depending on their definition [ 3 , 4 ] and have an incidence rate of 0.6–1.0 per 100,000 women per year in the USA[ 2 ] inferring a lifetime risk of less than 1 in 1000. Assessment by intrinsic subtypes of 28 metaplastic breast tumours found the majority were claudin-low or basal-like intrinsic subtypes [ 5 ] with most being triple negative [ 2 ]. Metaplastic breast cancer has a poorer prognosis compared to other breast cancer pathologies [ 2 , 6 ] possibly due to greater propensity to haematogenous spread rather than lymphatic, in contrast to Triple Negative Breast Cancer (TNBC) of no special type [ 2 ].…”

“…Assessment by intrinsic subtypes of 28 metaplastic breast tumours found the majority were claudin-low or basal-like intrinsic subtypes [ 5 ] with most being triple negative [ 2 ]. Metaplastic breast cancer has a poorer prognosis compared to other breast cancer pathologies [ 2 , 6 ] possibly due to greater propensity to haematogenous spread rather than lymphatic, in contrast to Triple Negative Breast Cancer (TNBC) of no special type [ 2 ]. Previous reports of treatment have also shown lower response rates to chemotherapy than would be expected for TNBC, perhaps suggesting a lower ‘BRCAness’ phenotype [ 2 ].…”

“…Metaplastic breast cancer has a poorer prognosis compared to other breast cancer pathologies [ 2 , 6 ] possibly due to greater propensity to haematogenous spread rather than lymphatic, in contrast to Triple Negative Breast Cancer (TNBC) of no special type [ 2 ]. Previous reports of treatment have also shown lower response rates to chemotherapy than would be expected for TNBC, perhaps suggesting a lower ‘BRCAness’ phenotype [ 2 ]. Up until now there has been no comprehensive assessment of more than a handful of metaplastic breast cancers for germline pathogenic variants in BRCA1 or BRCA2 .…”

“…Clearly more data is required on testing those with later onset metaplastic breast cancers. Poly-ADP ribose polymerase inhibitors (PARPi) have demonstrated activity in both adjuvant and metastatic settings in germline BRCA1 and BRCA2 Pathogenic Variant carriers and the diagnosis of metaplastic breast cancer should certainly not dissuade clinicians from ordering germline testing if other local criteria are met [ 2 ]. The relative absence of variants in BRCA2 in this study should not deter testing in this gene as they have also been reported and indeed shown to respond to PARPi [ 12 ].…”