The triple negative breast cancer drugs graveyard: a review of failed clinical trials 2017-2022

ABSTRACT

Introduction

Triple-negative breast cancer (TNBC) accounts for 15–20% of breast cancers (BC) and has the worst prognosis. It is characterized by the absence of both hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2). TNBC has more limited therapeutic options compared to other subtypes, meaning that there is still a long way to go to discover target treatments.

Areas covered

Our review aims to summarize phase II/III clinical trials enrolling patients with TNBC that have been published between 2017 and 2022 but failed to reach their primary endpoint. We here try to emphasize the limitations and weaknesses noted in negative studies and to point out unexpected results which might be useful to enhance the therapeutic approach to TNBC disease.

Expert opinion

A deeper understanding of the mechanisms behind TNBC heterogeneity allowed to enhance the knowledge of new prognostic and predictive biomarkers of response. However, it is also through several failed clinical trials that we were able to define new therapeutic approaches which improved TNBC patients’ clinical outcomes. Nowadays, we still need to overcome several difficulties to fully recognize different intracellular and extracellular pathways that crosstalk in TNBC and the mechanisms of resistance to identify novel tailored-patients’ therapies.

KEYWORDS:

• combined treatments
• failed clinical trials
• targeted therapy
• triple-negative breast cancer

Article highlights

• TNBC is characterized by molecular heterogeneity, and several pathways are involved in carcinogenesis, metastasis spreading, and resistance to drugs. Novel approaches such as ICIs, PARP inhibitors, and more recently ADCs have improved the prognosis of TNBC patients.

• Chemotherapy remains the cornerstone of TNBC treatments, but several compounds failed in providing a benefit to TNBC patients. Anthracycline, taxane, and platinum-based chemotherapy remain the standard for neo/adjuvant therapy, while the role of platinum in the metastatic setting is not yet clarified.

• Immunotherapy provided positive clinical results only in combination with chemotherapy.

• PARP inhibitors have low efficacy in HRD and gBRCA wild-type patients.

• PI3K/AKT and MAPK pathway inhibitors failed to demonstrate antitumor activity, despite the strong biological rationale for their use.

• With the exception of ADCs, many other molecules that act on transmembrane receptors and downstream signaling have failed to demonstrate efficacy.

• Prospective studies are always needed to clarify the best therapeutic approaches for patients considering the molecular heterogeneity that characterizes triple-negative disease.

This box summarizes key points contained in the article.

Abbreviations

ABC, ATP-binding cassette;

AC, anthracycline plus cyclophosphamide;

ADC, antibody-drug conjugates;

AMPK, AMP-activated protein kinase;

AR, androgen receptor;

ATR, ataxia telangiectasia-mutated- and Rad3-related kinase;

AurA, Aurora kinase;

BC, breast cancers;

BL, basal-like;

bsABs, bispecific antibodies;

CBR, clinical benefit rate;

CDK, cyclin-dependent kinase,

CHK1 checkpoint kinase 1;

CHK2, checkpoint kinase 2;

CSC, cancer stem cells

CTLA4, cytotoxic T-lymphocyte-associated protein 4;

DAR, drug antibody ratio;

DDFS, distant disease free survival;

DFS, disease free survival;

EFS, event-free survival;

EGF, epidermal growth factor;

EGFR, EGF receptor;

ER, estrogen receptor;

ERK, extracellular signal-regulated kinase;

Fab, fragment antigen binding;

FGF, fibroblast growth factor;

FGFR, fibroblast growth factor receptor;

FRα, folate receptor alpha;

gBRCA, germline BRCA;

gpNMB, glycoprotein non-metastatic B;

HDAC, histone deacetylases

HDACi, HDAC inhibitors

HER2, human epidermal growth factor receptor 2;

HR, hormone receptor;

HRR, homologous recombination repair;

HRRd, homologous recombination repair deficiency;

HSP90, heat shock protein.

ICI, immune-checkpoint inhibitors;

iDFS, invasive disease free survival;

ITT, intention to treat; MAPK, mitogen-activated protein kinase;

JAK/STAT, Janus kinase-signal transducer and activator of transcription;

LAR, luminal androgen receptor;

LN, lymph node;

M, mesenchymal;

mAB, monoclonal antibody;

MAPK, mitogen-activated protein kinase;

MDR1, multidrug resistance protein 1

MEK, mitogen-activated ERK kinase;

mTNBC, metastatic triple-negative breast cancer;

mTOR, mammalian target of rapamycin;

NACT, neoadjuvant chemotherapy;

NF-kB, nuclear factor kappa-light-chain-enhancer of activated B cells; OR, odds ratio;

ORR, overall response rate;

OS, overall survival;

PALB2, partner and localizer of BRCA2

PARP; poly-(ADP-ribose) polymerase;

PARPi, PARP inhibitors;

pCR, pathological complete response;

PDGF, platelet-derived growth factor;

PD-L1, programmed death-ligand 1;

PFS, progression-free survival;

PgR, progesterone, receptor;

PI3K, phosphatidylinositol 3-kinase;

PLK1, phosphorylation of Polo-Like Kinase 1;

PM(Cb) weekly paclitaxel plus non-pegylated liposomal doxorubicin and carboplatin;

PTEN, tensin homologue deleted on chromosome 10;

TILs, tumor-infiltrating lymphocytes;

TMB, tumor mutational burden;

TME, tumor microenvironment;

TNBC, triple-negative breast cancer;

TPC, treatment physician’s choice;

Trop-2, trophoblast cell surface antigen 2;

VEGF, vascular endothelial growth factor;

VEGFR, VEGF receptor;

Declaration of interest

GC received honoraria for speaker, consultancy, or advisory rule from AstraZeneca, Roche, Pfizer, Novartis, Seattle Genetics, Lilly, Ellipses Pharma, Foundation Medicine, Daiichi Sankyo, and Samsung. 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 apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.