Omitting Axillary Dissection in Node-Positive Breast Cancer: Insights from the SENOMAC Trial

Abstract

In breast cancer management, the standard approach for patients with sentinel-node metastases often includes completion axillary-lymph-node dissection (ALND) to mitigate the risk of residual cancer. However, recent advancements and trials, notably the SENOMAC trial, have examined whether this extensive procedure is necessary when sentinel-node biopsy alone could suffice. The SENOMAC trial, conducted across five countries, assessed the noninferiority of omitting ALND in favor of sentinel-node biopsy alone for patients with clinically node-negative primary breast cancer and sentinel-node macrometastases. This review synthesizes the trial’s findings, which indicate that omission of ALND does not compromise recurrence-free survival compared to the traditional approach, offering a potential paradigm shift in surgical practice for early-stage breast cancer patients.

Introduction

The management of axillary lymph nodes in breast cancer has undergone significant evolution over the past few decades. Traditionally, completion axillary-lymph-node dissection (ALND) was the gold standard for patients with sentinel-node metastases. This approach aimed to ensure comprehensive cancer control and prevent recurrence by removing all potentially affected lymph nodes. However, the necessity of this invasive procedure has been questioned in recent years due to advances in adjuvant therapies and more precise radiation techniques.

The SENOMAC trial represents a pivotal study in this context, evaluating whether the omission of ALND is a viable option for patients with clinically node-negative breast cancer who have sentinel-node macrometastases. The trial's focus on recurrence-free survival as the primary endpoint and its large-scale, multi-national design provide valuable insights into the efficacy and safety of this modified surgical approach. This review will delve into the methodology, results, and implications of the SENOMAC trial, highlighting its potential to influence clinical practice and patient outcomes in breast cancer treatment.

Literature Review

Historical Context and Rationale for Axillary Dissection

Axillary lymph node dissection (ALND) has long been a fundamental component of breast cancer management. Historically, this invasive procedure aimed to comprehensively address potential cancer spread by removing all axillary lymph nodes. The rationale for ALND was rooted in early studies that demonstrated a reduction in local recurrence rates and an improvement in overall survival for breast cancer patients with positive lymph nodes. For instance, seminal research by Veronesi et al. and Fisher et al. established that extensive axillary dissection could significantly impact disease outcomes.

However, as breast cancer treatment evolved, the approach to axillary management began to shift. The advent of sentinel-node biopsy (SNB) offered a less invasive alternative with promising results. Despite this, ALND remained a standard practice due to the belief that thorough surgical intervention was necessary to ensure comprehensive cancer control.

Advances in Sentinel-Node Biopsy

The sentinel-node biopsy (SNB) technique represents a major advancement in breast cancer surgery. Developed in the 1990s, SNB involves identifying and removing the sentinel lymph node—the first node to which cancer cells are likely to spread. This method aims to provide accurate staging information while minimizing surgical morbidity. Key studies, including those by Krag et al. and Giuliano et al., demonstrated the effectiveness of SNB in accurately staging axillary involvement and predicting patient outcomes.

Research has shown that SNB can achieve similar diagnostic accuracy to ALND while significantly reducing the risk of surgical complications. For example, the ACOSOG Z0011 trial revealed that patients with early-stage breast cancer and one or two positive sentinel nodes did not experience worse outcomes with the omission of ALND, provided they received adjuvant radiation therapy. This finding paved the way for a shift towards less invasive surgical approaches in breast cancer management.

Evolving Evidence and the Role of Radiation Therapy

The role of adjuvant radiation therapy in breast cancer has become increasingly significant. Studies have demonstrated that targeted radiation to the axillary region can be an effective alternative to ALND in managing lymphatic spread. The EORTC 10981-22023 AMAROS trial and the NSABP B-32 trial highlighted the effectiveness of axillary radiation therapy in reducing the risk of recurrence for patients with sentinel-node involvement.

Adjuvant radiation therapy has been shown to complement other treatment modalities, including systemic therapies, in managing breast cancer. It provides a targeted approach to address potential residual disease in the axillary region without the need for extensive surgical intervention. As such, radiation therapy has become a critical component of modern breast cancer treatment strategies, particularly for patients who may be candidates for omitting ALND.

Comparative Effectiveness of Sentinel-Node Biopsy versus ALND

The comparative effectiveness of sentinel-node biopsy versus ALND has been a subject of extensive research. Studies comparing the two approaches have consistently shown that SNB can provide equivalent or superior outcomes in terms of disease control and overall survival while reducing surgical complications. For instance, the NSABP B-32 trial demonstrated that patients who underwent SNB alone had comparable rates of disease-free survival and overall survival compared to those who underwent ALND.

This evidence supports the use of SNB as a viable alternative to ALND in specific patient populations, particularly those with early-stage breast cancer and limited sentinel-node involvement. The ability to achieve similar outcomes with less invasive surgery aligns with current trends in personalized medicine, where treatment strategies are tailored to individual patient needs and preferences.

Integration of Personalized Medicine and Targeted Therapies

The integration of personalized medicine and targeted therapies into breast cancer treatment has further influenced the management of axillary lymph nodes. Advances in genomic profiling and biomarker identification have enabled clinicians to tailor treatment plans based on individual patient characteristics and tumor profiles. This personalized approach allows for more precise decision-making regarding the necessity of ALND and the use of adjuvant therapies.

For example, genomic assays such as Oncotype DX and MammaPrint provide valuable information on the risk of recurrence and the potential benefit of adjuvant treatments. This information can guide decisions about the need for additional surgical interventions, including ALND, and help determine the most appropriate treatment strategy for each patient.

Emerging Research and Future Directions

Ongoing research continues to explore the optimal management of axillary lymph nodes in breast cancer. Emerging studies focus on refining surgical techniques, enhancing radiation therapy protocols, and incorporating novel therapeutic agents into treatment regimens. Advances in imaging technologies, such as high-resolution ultrasound and magnetic resonance imaging (MRI), are also contributing to improved staging and treatment planning.

Methodology

The SENOMAC trial was a noninferiority study designed to assess the impact of omitting completion axillary-lymph-node dissection (ALND) in favor of sentinel-node biopsy alone in patients with clinically node-negative primary breast cancer and sentinel-node macrometastases. Conducted across five countries between January 2015 and December 2021, the trial aimed to determine if sentinel-node biopsy alone could achieve comparable outcomes to ALND in terms of recurrence-free survival.

Participants and Randomization

The trial enrolled 2766 patients who met the inclusion criteria of having clinically node-negative T1 to T3 breast cancer, with T1 tumors ≤20 mm, T2 tumors 21 to 50 mm, and T3 tumors >50 mm in the largest dimension. Participants had one or two sentinel-node macrometastases, defined as metastases >2 mm in size. The randomization process assigned participants in a 1:1 ratio to either completion ALND or sentinel-node biopsy alone, ensuring a balanced comparison between the two approaches.

Interventions and Treatment Protocols

Patients in the sentinel-node biopsy-only group underwent only the initial sentinel-node biopsy procedure, with no additional axillary dissection. The ALND group, on the other hand, received completion ALND in addition to the sentinel-node biopsy. Both groups were treated according to national adjuvant treatment guidelines, which included chemotherapy, hormone therapy, and radiation therapy.

Endpoints and Statistical Analysis

The primary endpoint of the SENOMAC trial was overall survival, but the prespecified secondary endpoint was recurrence-free survival. To demonstrate noninferiority of sentinel-node biopsy alone, the upper boundary of the confidence interval for the hazard ratio for recurrence or death needed to be below 1.44. The trial utilized per-protocol and modified intention-to-treat analyses to assess outcomes, with a median follow-up period of 46.8 months.

Results

Study Population

Out of the 2766 enrolled patients, 2540 completed the trial according to protocol. In this cohort, 1335 patients were assigned to the sentinel-node biopsy-only group, while 1205 patients underwent completion ALND. Radiation therapy, including nodal target volumes, was administered to 1192 of 1326 patients (89.9%) in the sentinel-node biopsy-only group and 1058 of 1197 patients (88.4%) in the ALND group.

Recurrence-Free Survival

The median follow-up period was 46.8 months, with a range from 1.5 to 94.5 months. Among the 191 patients who experienced recurrence or death, the estimated 5-year recurrence-free survival rate was 89.7% (95% confidence interval [CI], 87.5 to 91.9) in the sentinel-node biopsy-only group. In comparison, the 5-year recurrence-free survival rate for the ALND group was 88.7% (95% CI, 86.3 to 91.1). The hazard ratio for recurrence or death, adjusted for country-specific factors, was 0.89 (95% CI, 0.66 to 1.19), indicating that the sentinel-node biopsy-only approach was significantly below the prespecified noninferiority margin (P<0.001).

Complications and Adverse Events

The trial also monitored complications associated with both surgical approaches. The incidence of adverse events related to axillary surgery, such as lymphedema and shoulder dysfunction, was notably lower in the sentinel-node biopsy-only group. This outcome highlights the potential benefits of reducing the extent of surgical intervention.

Conclusion

The SENOMAC trial provides robust evidence supporting the omission of completion axillary-lymph-node dissection in patients with clinically node-negative breast cancer and sentinel-node macrometastases. The study demonstrates that sentinel-node biopsy alone is noninferior to ALND in terms of recurrence-free survival, suggesting that a less invasive surgical approach can be equally effective in managing early-stage breast cancer with sentinel-node involvement.

The results have significant implications for clinical practice, offering a potential shift towards more conservative surgical strategies that can reduce patient morbidity without compromising treatment efficacy. By aligning with current trends in personalized medicine and patient-centered care, these findings support a paradigm shift in the management of axillary lymph nodes in breast cancer.

Discussion

Clinical Implications

The SENOMAC trial’s findings have transformative implications for breast cancer treatment. Traditionally, ALND has been considered essential for comprehensive axillary staging and cancer control. However, the evidence from this study suggests that sentinel-node biopsy alone, coupled with appropriate adjuvant therapies, can achieve comparable outcomes in terms of recurrence-free survival. This approach not only minimizes surgical morbidity but also aligns with evolving standards of care that emphasize reducing the invasiveness of treatment while maintaining efficacy.

Comparative Analysis with Previous Studies

The results of the SENOMAC trial are consistent with findings from previous studies that have explored less invasive surgical options. For instance, the NSABP B-32 and AMAROS trials highlighted the effectiveness of radiation therapy in reducing the need for extensive axillary dissection. By integrating these findings, the SENOMAC trial reinforces the potential for sentinel-node biopsy alone to serve as a viable alternative to ALND, particularly in patients who receive comprehensive adjuvant therapy.

Limitations and Considerations

While the SENOMAC trial provides compelling evidence, there are some limitations to consider. The trial’s median follow-up period of 46.8 months, while adequate for assessing recurrence-free survival, may not capture long-term survival outcomes or late-onset complications. Additionally, the study population was predominantly from high-income countries, which may limit the generalizability of the findings to diverse patient demographics and healthcare settings.

Patient Quality of Life

One of the key benefits of omitting ALND is the potential improvement in quality of life for patients. The reduction in surgical interventions can decrease the risk of complications such as lymphedema and shoulder dysfunction, which are associated with traditional axillary dissection. Future research should explore how these outcomes translate into long-term quality-of-life improvements and patient satisfaction.

Future Prospects

Long-Term Follow-Up and Additional Research

To fully understand the long-term impact of omitting ALND, extended follow-up studies are necessary. Future research should focus on assessing overall survival, late-onset complications, and patient-reported outcomes to provide a comprehensive evaluation of the benefits and risks associated with sentinel-node biopsy alone. Additionally, studies investigating the integration of advanced imaging and personalized treatment strategies could offer further insights into optimizing breast cancer management.

Exploring Diverse Patient Populations

Future research should also include diverse patient populations to evaluate the generalizability of the SENOMAC trial’s findings. Studies in varying healthcare contexts and among different demographic groups can help determine whether the benefits of omitting ALND extend across diverse patient populations and healthcare systems.

Integration of Advanced Technologies

The integration of advanced imaging technologies, such as molecular imaging and artificial intelligence, could enhance the precision of sentinel-node biopsy and further refine surgical decision-making. Future trials should explore how these technologies can be combined with less invasive surgical approaches to improve outcomes and tailor treatment to individual patient needs.

Personalized Medicine and Treatment Approaches

As the field of personalized medicine continues to evolve, future research should focus on developing tailored treatment strategies based on individual patient profiles. By incorporating genetic, molecular, and clinical data, personalized approaches can optimize treatment efficacy while minimizing unnecessary interventions.

Patient-Centered Care and Shared Decision-Making

The SENOMAC trial underscores the importance of patient-centered care and shared decision-making in breast cancer treatment. Future research should explore how involving patients in treatment decisions, considering their preferences and values, can enhance outcomes and align with personalized treatment goals.

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