mTNBC: Approaches for Advanced Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) is an aggressive subtype that lacks estrogen, progesterone, and HER2 receptors, making it more challenging to treat than other breast cancers. When TNBC progresses to a metastatic stage (mTNBC), treatment options become more limited, and prognosis worsens. However, advances in research have introduced new therapeutic strategies aimed at improving outcomes.

Emerging treatments now include targeted agents and immunotherapies alongside traditional chemotherapy, offering hope for better disease control. Supportive care also plays a crucial role in managing symptoms and maintaining quality of life.

Molecular Background

TNBC is defined by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression, but its molecular complexity extends beyond these characteristics. Unlike hormone receptor-positive or HER2-amplified breast cancers, TNBC lacks a singular dominant oncogenic driver, making it a heterogeneous disease with multiple molecular subtypes. Gene expression profiling has identified distinct TNBC subgroups, including basal-like 1 and 2, mesenchymal, and luminal androgen receptor (LAR) subtypes. The basal-like subtypes, which account for most TNBC cases, are highly proliferative and frequently harbor TP53 mutations, while the LAR subtype exhibits androgen receptor dependency, suggesting potential responsiveness to androgen-targeted therapies.

The genomic landscape of TNBC is marked by frequent mutations in tumor suppressor genes, particularly TP53, which is altered in approximately 80% of cases. This mutation leads to genomic instability and unchecked cell cycle progression, contributing to the disease’s aggressive nature. Additionally, defects in DNA damage repair pathways, such as those involving BRCA1 and BRCA2, are common in a subset of TNBC cases. These deficiencies create reliance on alternative DNA repair mechanisms, making tumors more susceptible to agents like poly (ADP-ribose) polymerase (PARP) inhibitors. Beyond BRCA mutations, homologous recombination deficiency (HRD) is observed in a broader group of TNBC patients, expanding the potential for targeted therapeutic interventions.

Epigenetic alterations also play a role in TNBC pathogenesis, influencing gene expression without altering the DNA sequence. Aberrant DNA methylation patterns, histone modifications, and dysregulated non-coding RNAs contribute to tumor progression and resistance to therapy. For instance, hypermethylation of the BRCA1 promoter can lead to gene silencing, mimicking the effects of BRCA1 mutations and conferring sensitivity to DNA-damaging agents. Similarly, dysregulated microRNAs (miRNAs) involved in cell cycle regulation and apoptosis affect tumor growth and treatment response. These epigenetic changes not only provide insights into disease mechanisms but also present potential targets for novel therapies.

Genetic Variations

The genetic landscape of mTNBC is shaped by mutations and structural alterations that drive tumor progression, therapeutic resistance, and disease heterogeneity. TP53 mutations, present in approximately 80% of cases, are associated with increased genomic instability. This loss of functional p53, a key regulator of cell cycle arrest and apoptosis, allows unchecked proliferation and the accumulation of additional genetic aberrations, accelerating tumor evolution. Unlike other breast cancer subtypes driven by dominant oncogenic alterations, mTNBC features a diverse set of coexisting mutations, complicating treatment strategies.

Deficiencies in DNA damage repair mechanisms play a central role in mTNBC. BRCA1 and BRCA2 mutations, found in about 10-20% of TNBC cases, disrupt homologous recombination (HR) repair, making tumor cells more dependent on alternative repair pathways. This vulnerability has been leveraged with PARP inhibitors, which induce synthetic lethality in BRCA-mutant tumors by further impairing DNA repair. However, BRCA mutations represent only a subset of tumors with HRD, as other genetic alterations—such as RAD51C, PALB2, and ATM mutations—also contribute to defective DNA repair. HRD extends beyond germline mutations, with BRCA1 promoter methylation serving as another mechanism of HR loss. Identifying HRD-positive tumors through genomic profiling has become increasingly relevant for guiding treatment selection, particularly with platinum-based chemotherapy and PARP inhibitors.

The PI3K/AKT/mTOR signaling pathway, frequently altered in mTNBC, influences tumor behavior. Activating mutations in PIK3CA, found in approximately 10-15% of TNBC cases, drive oncogenic signaling that promotes cell survival and proliferation. Loss-of-function mutations in PTEN, a negative regulator of this pathway, further contribute to pathway dysregulation. These alterations have been associated with resistance to chemotherapy and targeted therapies, prompting investigations into PI3K or AKT inhibitors in combination with standard treatments. Given TNBC’s heterogeneity, combination strategies tailored to specific genetic profiles may be necessary to achieve meaningful therapeutic benefits.

Clinical Signs

mTNBC presents with a range of clinical signs that reflect both the aggressive nature of the disease and the specific organs affected by distant spread. Unlike localized TNBC, where symptoms are confined to the breast and regional lymph nodes, mTNBC manifests through systemic and site-specific symptoms depending on metastatic burden.

The most common initial presentation involves a palpable breast mass that is firm, irregular, and rapidly enlarging. Unlike hormone receptor-positive breast cancers, which may grow more indolently, TNBC tumors tend to be highly proliferative. Skin involvement, including ulceration, erythema, and peau d’orange, can indicate extensive local invasion. Axillary lymphadenopathy is frequently observed, often appearing as hard, fixed nodes that suggest regional spread. Given TNBC’s aggressive nature, distant metastases can develop early, sometimes before a primary tumor is detected.

Common metastatic sites include the lungs, liver, bones, and brain. Pulmonary metastases may present with persistent cough, dyspnea, or pleural effusion. Hepatic metastases can cause right upper quadrant pain, hepatomegaly, and elevated liver enzymes, sometimes accompanied by jaundice. Bone metastases, although less frequent in TNBC compared to other breast cancer subtypes, can result in severe skeletal pain, pathological fractures, and spinal cord compression. Brain metastases, disproportionately more common in TNBC, often lead to neurological deficits such as headaches, seizures, vision changes, and cognitive impairment.

Imaging and Laboratory Tests

Accurate diagnosis and monitoring of mTNBC rely on imaging and laboratory tests to assess tumor burden, guide treatment decisions, and detect disease progression.

Computed tomography (CT) scans are frequently used to evaluate visceral metastases, particularly in the lungs and liver. Contrast-enhanced CT provides detailed anatomical visualization, helping clinicians assess tumor size, organ involvement, and response to therapy. For suspected bone metastases, whole-body bone scintigraphy or positron emission tomography (PET) combined with CT (PET-CT) can detect osteolytic lesions. Magnetic resonance imaging (MRI) is particularly valuable for detecting brain metastases, which occur frequently in TNBC. Given its superior soft tissue resolution, MRI is often recommended when neurological symptoms arise.

Laboratory tests complement imaging findings. Serum tumor markers such as carcinoembryonic antigen (CEA) and cancer antigen 15-3 (CA 15-3) are sometimes monitored, though their utility in TNBC is limited. Circulating tumor DNA (ctDNA) analysis has emerged as a promising tool for detecting minimal residual disease and tracking tumor evolution in real time. Liquid biopsy techniques, which analyze ctDNA fragments shed by tumor cells into the bloodstream, offer a non-invasive method for identifying genetic alterations that may inform targeted therapy selection. Comprehensive genomic profiling of tumor tissue remains essential in evaluating HRD status, which can influence treatment choices.

Treatment Approaches

Managing mTNBC requires systemic therapies tailored to tumor biology. Unlike other breast cancer subtypes, mTNBC lacks hormone receptors and HER2 amplification, limiting the efficacy of endocrine and HER2-targeted treatments. The therapeutic landscape has evolved significantly, incorporating chemotherapy, targeted agents, and immunotherapy.

Chemotherapy

Cytotoxic chemotherapy remains a primary treatment due to its broad activity against rapidly dividing cells. Platinum-based agents, such as carboplatin and cisplatin, are particularly effective in tumors with HRD, including those with BRCA1/2 mutations. These drugs induce DNA cross-linking, leading to cell death in tumors with defective DNA repair mechanisms.

Taxanes, including paclitaxel and docetaxel, disrupt microtubule dynamics, inhibiting cell division and inducing apoptosis. Their efficacy in mTNBC has been well established, often as a first-line treatment. Eribulin, a microtubule inhibitor, has also shown efficacy in later-line settings, particularly in heavily pretreated patients.

Targeted Agents

PARP inhibitors, such as olaparib and talazoparib, have demonstrated clinical benefit in patients with germline BRCA1/2 mutations. Inhibitors of the PI3K/AKT/mTOR pathway, including ipatasertib and capivasertib, have shown activity in combination with chemotherapy, particularly in tumors with PIK3CA or PTEN mutations.

Immunotherapy

Immune checkpoint inhibitors (ICIs), such as pembrolizumab and atezolizumab, block PD-1/PD-L1 interactions, restoring T-cell activity. The KEYNOTE-355 trial demonstrated that pembrolizumab combined with chemotherapy significantly improved survival in PD-L1-positive mTNBC.

Supportive Strategies

Beyond direct tumor-targeting treatments, supportive care plays a crucial role in managing mTNBC by alleviating symptoms and improving quality of life.