Understanding Luminal B Breast Cancer: Molecular Characteristics, Treatment Approaches, and Future Directions

Table of Contents

• Introduction: A New Understanding of Breast Cancer Types
• Molecular Characteristics of Luminal B Breast Cancer
• Defining Luminal B in Clinical Practice
• Clinical Behavior and Prognosis
• Response to Chemotherapy
• Response to Endocrine Therapy
• Clinical Implications for Patients
• Limitations of Current Knowledge
• Future Research Directions
• Source Information

Introduction: A New Understanding of Breast Cancer Types

In the early 2000s, groundbreaking research transformed our understanding of breast cancer. Scientists discovered that what was once considered a single disease actually comprises at least four distinct molecular subtypes with different characteristics, behaviors, and treatment responses. These intrinsic molecular subtypes were defined as: basal-like, human epidermal growth factor receptor 2 (HER2)-enriched, and luminal A and B subtypes.

Additional studies further separated luminal breast cancers into two important subgroups. Luminal A tumors were characterized by high expression of estrogen-related genes and low expression of proliferation-related genes. In contrast, luminal B cancers showed lower expression of estrogen receptor (ER) genes, lower expression of progesterone receptor (PgR) genes, and higher expression of proliferation markers and cell cycle-associated genes.

Approximately 20% of luminal B tumors are HER2-positive by both mRNA levels and immunohistochemistry (IHC) testing. This molecular distinction has profound implications for how patients are treated and what outcomes they can expect.

Molecular Characteristics of Luminal B Breast Cancer

Luminal B breast cancer exhibits unique genetic features that distinguish it from other subtypes. Researchers have identified specific patterns of gene copy number alterations (CNAs), DNA methylation changes, and somatic point mutations that characterize this aggressive form of breast cancer.

High-level DNA amplifications and chromosomal abnormalities occur more frequently in luminal B cancers than in other subtypes. The discovery of recurrent genome CNAs led to identifying specific oncogenes that drive this subtype's behavior. The ZNF703 oncogene, for example, induces cellular proliferation independently of estrogen stimulation and is associated with worse clinical outcomes. This oncogene stimulates genes related to WNT and NOTCH signaling pathways, which regulate the self-renewal of breast tumor-initiating cells (TICs).

The METABRIC (Molecular Taxonomy of Breast Cancer International Consortium) study, which integrated genomic and transcriptomic profiling of 2,000 breast tumors, identified ten molecular subtypes with different clinical behaviors. Luminal B breast cancers clustered in several of these integrative clusters (IntClusts 1, 6, and 9), each characterized by specific genetic abnormalities.

Next-generation sequencing studies have further elucidated luminal B's molecular uniqueness:

• Mutation patterns: Luminal B cancers show lower frequency of PIK3CA mutations (29% vs 45%) and higher frequency of TP53 mutations (29% vs 12%) compared to luminal A cancers
• GATA3 mutations: Occur in approximately 15% of luminal B cancers, with different mutation types than those found in luminal A tumors
• RUNX1 mutations: Loss-of-function mutations in this gene are associated with poorly differentiated breast cancer and features of endocrine resistance

These molecular differences confirm that luminal A and B breast cancers are distinct entities with specific oncogenic drivers, rather than simply more or less proliferative varieties of luminal tumors.

Defining Luminal B in Clinical Practice

In daily clinical practice, doctors use several methods to identify luminal B breast cancer. The most accurate approach uses gene expression classifiers like the PAM50 signature, which analyzes 50 genes involved in proliferation, ER signaling, HER2 status, and basal characteristics. This signature has been implemented in a clinical assay called Prosigna that can be performed on standard tissue samples.

However, because molecular testing remains relatively expensive and technically complex, most clinicians rely on surrogate markers using immunohistochemistry (IHC). Researchers have proposed several IHC-based definitions for classifying luminal B breast cancer, primarily focusing on proliferation markers:

Proposed IHC Markers for Luminal B Classification:

• Cheang et al: ER positive, HER2 negative, Ki67 ≥ 14%
• Prat et al: ER positive, PgR < 20%, HER2 negative, Ki67 ≥ 14%
• Goldhirsch et al: ER positive, HER2 negative, Ki67 ≥ 14%
• Harbeck et al: ER positive, HER2 negative, Ki67 ≥ 20-25%

The challenge with using Ki67 as a marker is that proliferation exists on a continuum rather than as an on/off switch. Different studies have recommended cutoffs ranging from 13.25% to 25%, and there's significant variation in how pathologists evaluate and interpret Ki67 staining. In one study, the concordance rate for grade classification among three different pathologists was only 43%.

Progesterone receptor (PgR) status has also been used to define luminal B cancer. Patients with ER-positive, HER2-negative tumors with Ki67 ≥ 14% and PgR < 20% had worse prognosis than those with PgR ≥ 20%. The hazard ratio for relapse was 1.96, meaning nearly double the risk.

Clinical Behavior and Prognosis

Luminal B breast cancer demonstrates aggressive clinical behavior with prognosis similar to HER2-enriched and basal-like subtypes, while luminal A breast cancer has a more favorable outcome. This difference manifests in distinct patterns of recurrence and metastasis.

Patients with luminal B cancer experience increased relapse rates in the first five years after diagnosis. In a study of 831 untreated node-negative patients, the hazard ratio for early metastasis (within 5 years) was 2.86 compared to luminal A cancers. This means luminal B patients had nearly triple the risk of early metastasis.

The pattern of metastatic spread also differs between subtypes. Luminal B cancers show predilection for bone metastasis and, to a lesser degree, lung metastasis. While luminal A cancers also frequently spread to bone, they show lower frequency of metastasis to other sites.

Gene expression profiling signatures provide prognostic information beyond standard clinicopathologic parameters. Most luminal A tumors are classified as low genomic risk, while luminal B cancers are often classified as high genomic risk. Multiple studies have shown that despite little overlap in their constituent genes, these prognostic signatures show significant overlap in their performance because they primarily measure proliferation patterns.

Response to Chemotherapy

Most luminal B cancers are classified as having high recurrence scores by Oncotype DX testing. The NSABP B-20 study showed that patients with high recurrence scores (≥31) derived substantial benefit from chemotherapy added to tamoxifen, with a hazard ratio of 0.26 for recurrence and an absolute decrease in distant recurrence rate of 27.6%.

In neoadjuvant studies, luminal tumors generally exhibit lower pathologic complete response (pCR) rates than HER2-enriched and triple-negative breast cancers. The pCR rates for luminal B cancers across multiple studies ranged from 1.4% to 15%, compared to 22-55% for HER2-positive tumors and 27-67% for basal-like cancers.

Despite the relatively low pCR rates, neoadjuvant chemotherapy appears effective in reducing tumor volume in luminal B cancers. Tumors with high prognostic signature values according to several gene expression profiling classifiers are associated with higher probability of pCR.

The St. Gallen consensus panel recommended that both anthracyclines and taxanes should be included in chemotherapy regimens for luminal B breast cancer. Three major prospective randomized trials—MINDACT, TAILORx, and RxPONDER—are currently testing the usefulness of gene signatures in predicting benefit from adjuvant chemotherapy in ER-positive breast cancer, with results expected between 2015 and 2017.

Response to Endocrine Therapy

The evidence supporting relatively lower benefit from endocrine therapy in the luminal B subtype comes from several important studies. An EBCTCG meta-analysis showed small benefits with tamoxifen in patients with low ER levels. In the BIG 1-98 trial, patients with lower ER levels had worse disease-free survival than those with high ER levels.

Dynamic changes in Ki67 expression during endocrine therapy can predict outcomes in luminal breast cancer. In the IMPACT trial, patients with higher Ki67 expression after 2 weeks of endocrine therapy had worse prognosis, and this was particularly evident in luminal B-like tumors.

The POETIC trial is currently evaluating whether Ki67 levels after 2 weeks of aromatase inhibitor therapy can predict long-term outcome better than baseline Ki67. Preliminary results show that on-treatment Ki67 is indeed a stronger predictor of recurrence-free survival.

Studies comparing different endocrine agents show mixed results in luminal B patients:

• In the ATAC trial, ER-positive/PgR-negative patients obtained greater relative benefit from anastrozole than from tamoxifen (HR 0.42)
• In BIG 1-98, high Ki67 predicted greater efficacy of letrozole over tamoxifen (HR 0.53)
• However, using the surrogate luminal B definition, no difference was seen between tamoxifen and letrozole

HER2-positive overexpression increases the risk of disease recurrence (relative risk 1.42) independently from the type of hormone treatment, suggesting no additional benefit from aromatase inhibitors over tamoxifen in this subgroup.

Clinical Implications for Patients

For patients diagnosed with luminal B breast cancer, this research has several important implications. First, accurate subtyping is crucial for determining appropriate treatment strategies. Patients should discuss comprehensive biomarker testing with their oncologists, including ER, PgR, HER2, and Ki67 status, and consider gene expression profiling when appropriate.

Treatment decisions should reflect the aggressive nature of luminal B disease. Most patients will benefit from chemotherapy in addition to endocrine therapy, particularly those with high recurrence scores or high proliferation indices. The combination of anthracyclines and taxanes is often recommended.

Endocrine therapy remains fundamental, but patients should understand that luminal B cancers may show相对 resistance to hormone treatment alone. Monitoring response through Ki67 changes after short-term endocrine therapy may help predict long-term outcomes and guide treatment adjustments.

Patients with HER2-positive luminal B disease may benefit from dual targeting of both hormonal and HER2 pathways. Clinical trials are ongoing to identify optimal combination strategies for these patients.

Limitations of Current Knowledge

Several important limitations affect our current understanding of luminal B breast cancer. The lack of standardized criteria for defining this subtype creates confusion in both research and clinical practice. Different studies use different Ki67 cutoffs (ranging from 14% to 25%), and there's significant inter-pathologist variability in Ki67 assessment.

Most evidence comes from retrospective analyses or subgroup analyses of larger trials not specifically designed to study luminal B cancer. This limits the strength of conclusions that can be drawn about optimal treatment strategies.

The relative contributions of proliferation, HER2 status, and hormone receptor expression to the luminal B phenotype are not fully understood. These factors may have different implications for treatment response and prognosis, but current classification systems often combine them.

Long-term data on treatment outcomes specifically for luminal B patients are limited, particularly regarding newer targeted agents and combination therapies.

Future Research Directions

Several ongoing research efforts aim to address current limitations and improve outcomes for luminal B breast cancer patients. The results of three major trials—MINDACT, TAILORx, and RxPONDER—will provide crucial information about using gene signatures to guide chemotherapy decisions in ER-positive disease.

Research into molecularly targeted agents holds particular promise for luminal B patients. Studies are investigating agents targeting specific pathways dysregulated in this subtype, including:

• PI3K/AKT/mTOR pathway inhibitors
• CDK4/6 inhibitors
• FGFR inhibitors
• HDAC inhibitors

Combination strategies targeting multiple pathways simultaneously may overcome the relative endocrine resistance observed in luminal B cancers. Several trials are testing endocrine therapy combined with targeted agents in both early and advanced settings.

Refining classification systems using integrated genomic data may lead to more precise patient stratification. The development of standardized, reproducible assays for proliferation assessment remains a priority for both research and clinical practice.

Source Information

Original Article Title: Luminal B Breast Cancer: Molecular Characterization, Clinical Management, and Future Perspectives

Authors: Felipe Ades, Dimitrios Zardavas, Ivana Bozovic-Spasojevic, Lina Pugliano, Debora Fumagalli, Evandro de Azambuja, Giuseppe Viale, Christos Sotiriou, and Martine Piccart

Publication: Journal of Clinical Oncology, Volume 32, Number 25, September 1, 2014

Note: This patient-friendly article is based on peer-reviewed research originally published in the Journal of Clinical Oncology. It preserves all significant findings, data points, and conclusions from the scientific publication while making the information accessible to educated patients.