SENOMAC Trial - Is the Answer Less Slice and Dice?

No one involved with Oncology for the Inquisitive Mind would ever claim to be a surgeon or even surgically inclined; several of us readily admit that we have the coordination and motor skills of a monkey without a cerebellum. However, every oncologist works intimately with our surgical colleagues, so being abreast (pun slightly intended) of new evidence regarding the surgical management of cancer. 

Since 2010, there has been a growing body of evidence that for people with clinically node-negative (cN0) breast cancer undergoing breast-conserving surgery and radiotherapy, in whom sentinel lymph-node biopsy had revealed one or two metastases. The Americal College of Surgeons Oncology Group (ACOSOG) Z0011 trial and the European Organisation for Research and Treatment of Cancer (EORTC) 10981-22023 AMAROS trial, among others, demonstrated no benefit of completion axillary lymph node dissection. As a result of these data, the use of “completion” axillary lymph node dissection has been decreasing worldwide.

This is an important development, given the significant morbidity associated with axillary lymph node dissection, most commonly in the form of lymphedoema, which can have a devastating impact on a patient’s functionality.

The SENOMAC trial, published in the New England Journal of Medicine on April 3 2024, was a large, prospective, phase III, confirmatory, non-inferiority study that aimed to validate data from these trials and confirm the non-inferiority of sentinel lymph node biopsy compared to axillary dissection in patients with early breast cancer.

The trial was conducted at 67 hospitals in Sweden, Denmark, Germany, Greece and Italy between 2015 and 2021. Patients were required to have cN0 breast cancer with a tumour (T) stage of T1-T3 with one or two sentinel-node macrometastases (>2mm in largest dimensions). Patients were ineligible if they had extra-axillary regional or distant metastases, a past history of invasive breast cancer, bilateral breast cancer and medical contraindications against radiation or systemic therapy.

In total, 1540 patients were included in the final data set (division below).

Image courtesy of New England Journal of Medicine

The primary end point was overall survival; this was changed from breast cancer-specific survival on the basis of a recommendation from the independent data and safety monitoring board. Secondary end points were recurrence-free survival, breast cancer-specific survival and patient-reported outcomes.

Clinical noninferiority was defined as a 5-year overall survival (OS) in the biopsy-alone group that was not worse by more than 2.5% when compared to the axillary dissection. For comparison, this margin is half that used in the ACOSOG Z0011 trial.

Image courtesy of New England Journal of Medicine

With a median follow-up of 46.8 months, the estimated 5-year overall survival in the biopsy-only group was 92.9% and 92.0% in the dissection group. The estimated 5-year cancer-specific survival was 97.1% in the biopsy group and 96.6% in the dissection group.

The number of confirmed recurrences was very small, with only 52 recurrence events in the biopsy-only group and 69 recurrence events in the control group. The vast majority of recurrences were distant (70.9% and 76.8%, respectively). The estimated 5-year disease-free survival was 89.7% in the investigation group and 88.7% in the control group.

After stratification by country, the hazard ratio for disease recurrence or death was 0.89 (p<0.001), which was significantly below the noninferiority margin. No examined subgroup suggested a benefit for axillary dissection over biopsy alone, though, to reiterate, the number of recurrence or mortality events was quite low.

The Bottom Line:

The SENOMAC trial added to the growing body of evidence that for patients with cN0 localised breast cancer of any histological subtype, there was no difference in OS or DFS between sentinel lymph node biopsy and completion axillary dissection. This is an excellent development for patients, as it reduces the risk of lymphoedema. While this was not a specific endpoint or area of examination in SENOMAC, the AMAROS trial demonstrated that lymphoedema was twice as likely to occur in patients who underwent axillary dissection compared to lymph node biopsy only.

It is important to note that this approach is not necessarily applicable to all early breast cancer patients. While no specific considerations were given to histological type, ER or HER2 positivity, or Ki67 percentage, the study specifically excluded patients with a T4 primary, clinical node positivity, or extra-axillary nodal disease. In addition, while male patients with breast cancer were allowed, only 10 male patients were enrolled over a 7-year period, which prevented subgroup analysis by gender. So, as ever, patient selection remains critical.

However, at the end of the day, improving our sophistication with patient selection for potentially morbid surgical procedures is never unwelcome. The SENOMAC study confirms that an axillary-sparing approach should be the standard practice in patients with T1-T3, cN0 breast cancer

Sources

de Boniface J, Tvedskov TF, Rydén L et al. Omitting Axillary Dissection in Breast Cancer with Sentinel-Node Metastases. N Engl J Med. 2024;390:1163-1175. DOI: 10.1056/NEJMoa2313487