Heterogeneity of triple-negative breast cancer: understanding the Daedalian labyrinth and how it could reveal new drug targets

ABSTRACT

Introduction

Triple-negative breast cancer (TNBC) is considered the most aggressive breast cancer subtype with the least favorable outcomes. However, recent research efforts have generated an enhanced knowledge of the biology of the disease and have provided a new, more comprehensive understanding of the multifaceted ecosystem that underpins TNBC.

Areas covered

In this review, the authors illustrate the principal biological characteristics of TNBC, the molecular driver alterations, targetable genes, and the biomarkers of immune engagement that have been identified across the subgroups of TNBC. Accordingly, the authors summarize the landscape of the innovative and investigative biomarker-driven therapeutic options in TNBC that emerge from the unique biological basis of the disease.

Expert opinion

The therapeutic setting of TNBC is rapidly evolving. An enriched understanding of the tumor spatial and temporal heterogeneity and the surrounding microenvironment of this complex disease can effectively support the development of novel and tailored opportunities of treatment.

KEYWORDS:

• ADC
• androgen receptor
• BRCAness
• epigenetics
• immunotherapy
• MAPK
• PI3K-AKT-mTOR
• TNBC subtypes
• TROP-2
• tumor heterogeneity

Article highlights

• TNBC is a heterogeneous disease comprising several subtypes characterized by histopathological, transcriptomic, and (epi)genomic features, which could represent potential actionable molecular targets.

• BRCAness and germline BRCA1/2 mutations are predictive factors for platinum salts and PARP-inhibitors effectiveness

• The combination of immune checkpoint inhibitors and chemotherapy is a significant therapeutic option in selected TNBC, both in the early and metastatic setting

• The antibody–drug conjugates sacituzumab govitecan, trastuzumab deruxtecan (in HER2-low TNBC) and datopotamab deruxtecan are promising therapeutic agents for metastatic TNBC

• Despite preclinical suggestions, neither anti-androgens for AR-expressing TNBC nor inhibitors targeting the PI3K/AKT/mTOR or the MAPK pathways have currently robust data to support their role in the clinical practice.

• Novel targeted, signaling-based therapies are urgently needed in the management of TNBC, exploiting its biological heterogeneity.

List of abbreviations

ADC, antibody drug–conjugate; AR, androgen receptor; BC, breast cancer; BL, Basal-like: CBR, clinical benefit rate; CI, confidence interval; CTLA-4, cytotoxic T-lymphocyte-associated antigen-4; ctDNA, circulating tumor DNA; EGFR, epidermal growth factor receptor; ER, estrogen receptor; gBRCAm, germline BRCA mutations; HER2, human epidermal growth factor receptor 2; HR, hazard ratio; HRD, homologous recombination deficiency; ICI, immune checkpoint inhibitor; IM, immunomodulatory; ITT, intention to treat; LAR, luminal androgen receptor; M, mesenchymal; MAPK, mitogen-activated protein kinase; MSL, mesenchymal stem-like; mTNBC, metastatic TNBC; ORR, overall response rate; PARP, poly(ADP-ribose) polymerase; pCR, pathologic complete response; PD-1, cell death protein-1; PD-L1, PD-ligand 1; PFS, progression-free survival; PgR, progesterone receptor; po, oral administration; PI3K, phosphoinositide-3-kinase; q.d., once a day; TNBC, triple-negative breast cancer; TN, triple-negative; Topo1, topoisomerase I; TPC, treatment of physician choice.

Declaration of interest

A Zambelli received honoraria for advisory board and consultancy form Novartis, AstraZeneca, Lilly, Daiichi Sankyo, MDS (Merck Sharp&Dome), Roche, Seagen, Exact Sciences, Gilaed, Istituto Gentili (all outside the submitted work).

E Agostinetto received Speaker fees from Eli Lilly and Support for attending medical conferences from Novartis, Roche, Eli Lilly, Genetic, Istituto Gentili (all outside the submitted work).

R De Sanctis received honoraria for advisory board consultancy form Novartis (outside the submitted work)

A Santoro received honoraria for advisory board and consultancy formBMS (Bristol-MyersSquibb), Servier, Gilead, Pfizer, Eisai, Bayer, MSD (Merck Sharp&Dome) Arqule, Sanofi and Speaker’s Bureau fees from Takeda, BMS (Bristol-Myers-Squibb), Roche, Abb-Vie, Amgen, Celgene, Servier, Gilead, AstraZeneca, Pfizer, Arqule, Eli-Lilly, Sandoz, Eisai, Novartis, Bayer, MSD (Merck Sharp & Dohme).

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

One reviewer is affiliated with a company that investigates novel drugs targeting specific drivers of malignant breast tumor growth and metastases. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

The research activity leading to this manuscript has received funding from Fondazione AIRC under 5 per mille 2019 - ID. 22759, program.