SLNB Omission in Early Breast Cancer: Clinical Implications of SOUND and INSEMA

The SOUND (NCT02167490) and INSEMA (NCT02466737) trials both evaluated the utility of sentinel lymph node biopsy (SLNB) in patients with early-stage breast cancer.^1,2 The studies were structured similarly, with notable differences being primary endpoint and tumor size eligibility criteria (clinical T1 vs T1-T2).

In the SOUND trial, the 5-year distant disease-free survival (DDFS) rate was 97.7% in the SLNB group vs 98.0% in the no axillary surgery group (HR, 0.84; 90% CI, 0.45-1.54). In the INSEMA trial, the estimated 5-year invasive disease-free survival rate was 91.9% (95% CI, 89.9%-93.5%) in the surgery omission group vs 91.7% (95% CI, 90.8%-92.6%) in the surgery group (HR, 0.91; 95% CI, 0.73-1.14).

Sunil Dutta, MD, spoke with CancerNetwork® about the importance of these trials in the radiation oncology field and how the results come into play when making treatment decisions. Additionally, he touched on topics such as regional nodal irradiation (RNI), balancing treatment and minimizing exposure to the heart and lungs, and the next steps when recurrence occurs.

Dutta is an assistant professor in the Department of Radiation Oncology at Emory University School of Medicine, and an editorial advisory board member for the journal ONCOLOGY’s® radiation oncology supplement, The RadOnc Review.

CancerNetwork: Can you provide a brief background on the SOUND and INSEMA trials and why they are relevant to today’s discussion?

Dutta: They are conceptually similar trials aimed at de-escalating axillary surgery. The SOUND and INSEMA trials were recently published, offering up to 6 years of follow-up, and represent a further evolution after the earlier phase 3 ACOSOG Z0011 trial [NCT00003855]. In that sense, these trials test whether we can omit surgical axillary staging altogether in selected patients.

In both trials, patients underwent preoperative staging, including clinical exam and imaging such as axillary ultrasound; if those lymph nodes were sonographically normal, women were [randomly assigned] to either SLNB or no axillary surgery. Nearly all of the patients received adjuvant whole breast radiation on both trials, with about 10% receiving partial breast irradiation on SOUND . While the inclusion criteria was quite broad outside of clinical staging, most women enrolled were over 50 years old with hormone receptor–positive disease and tumors that were less than 2 cm.

At the 5-to-6-year mark, neither trial showed a statistically significant difference in their primary outcomes. For the SOUND trial, the primary outcome was DDFS, whereas for INSEMA, it was invasive disease-free survival. Particularly notable was the extremely low rate of axillary recurrence, 1% or less, in both trials at 5 to 6 years follow-up. That has called into question: is there value in knowing the pathological nodal status, given that when you omit surgical staging of the axilla, there’s no difference in these important outcomes?

Do the outcomes of SOUND and INSEMA support the view that the axillary radiation dose delivered as part of a standard whole breast radiation therapy field is sufficient to sterilize low-volume nodal disease in a select population, thereby replacing the therapeutic role of SLND and axillary lymph node dissection in this setting?

I don’t have a definitive answer to that. The hypothesis, addressed in the INSEMA manuscript discussion, suggests that standard whole breast radiation fields provided about 80% of the prescription dose to the level 1 axilla, the first echelon of nodal drainage, in roughly half of the patient plans available for central review. Although the coverage isn’t 100%, this is in the region where surgeons typically perform SLNB. Variations naturally occur depending on patient anatomy. For example, women with larger breasts or higher body mass index often have breast tissue extending closer to the clavicle, inadvertently resulting in some dose coverage as high as the level 2 axilla.

Therefore, it is uncertain if it is the radiation that’s sterilizing it, considering this variation based on anatomy and physician field design, or if it’s the systemic therapy that they’re on, particularly hormone therapy. The big asterisk, too, is with breast cancer, especially hormone receptor–positive disease; most of these women are on endocrine therapy for 5 years. It’s possible that the endocrine therapy plus the radiation could control the disease up to 5 to 6 years, but after that, we don’t know. Typically, we do feel more comfortable with 10 to 15 years of follow-up to see if the disease is truly sterilized from the radiation in those cases.

In a patient who meets the criteria for SLNB omission but requires RNI for other high-risk features, do the trial results still support omitting SLNB, or does the plan for RNI render the SLNB decision moot?

This scenario is more straightforward. There are very few situations where someone would meet indications for RNI and still be eligible for the SOUND or INSEMA trial. Generally, when we recommend RNI upfront, prior to surgery, it’s because they have clinically involved appearing lymph nodes or they have a large tumor, over 5 cm, which would have excluded them from these trials. Fortunately, they don’t muddy that water, so if they’re meeting the criteria of RNI, they’re likely not to be eligible for that trial. The SLNB may be indicated for several reasons, such as measuring the response to neoadjuvant chemotherapy, but that would be a separate clinical pathway, though.

When treating the whole breast after omitting SLNB (based on SOUND/INSEMA criteria), what are your specific clinical target volume margin practices relative to the chest wall/axilla?

This is a debatable subject because it brings into question the idea of whether to use high tangents. High tangents involve using standard tangential fields, without adding a third supraclavicular field, and raising the superior border to up to, but not including, the humoral head. That became popular when I was in training, over 5 years ago. Two reasons contributed to its popularity: first, the Z0011 protocol analysis showed that half of the patients who received tangential radiation received high tangents (defined as ≤ 2 cm from the humeral head in that analysis). The question I ask is: was that because of those patients’ body habitus, or was that intentional by the radiation oncologists? That’s not documented anywhere, but based on INSEMA, which had stricter QA and prohibited high tangents, again about half of patients receive significant dose to axillary levels 1-2, which implies anatomy may play a larger role than physician intent.

Additionally, the concept of high tangents and covering the level 1-2 axilla has never been tested prospectively. Typically, trial protocols explicitly recommend treatment to the whole breast alone, or, if nodal treatment is indicated, adding a supraclavicular field. Personally, I don’t consider high tangents a standard-of-care radiation approach, although I have used them selectively in the past. Caution is advised because their use isn’t definitively supported by evidence. If nodal treatment is indicated, a dedicated supraclavicular field should be used. If there is no indication for nodal treatment, physicians should be comfortable treating only the breast, which is how most patients on Z0011, SOUND, and INSEMA were managed and still experienced great outcomes.

For patients eligible for SLNB omission, how do you manage the trade-off between ensuring adequate coverage of the level 1 axilla (as the assumed therapeutic dose) and minimizing dose-volume histogram parameters for critical structures like the heart and lung, especially for left-sided tumors?

When using high tangents, there is a slight increase in radiation exposure to the upper lung; However, this increase is minimal, and the overall lung dose remains low when treating the breast alone without intentional supraclavicular fields. Lung dose significantly increases when intentionally targeting the internal mammary node, which generally isn’t indicated in these patients. Although there is a slight increase with high tangents, it does not appreciably raise concerns about radiation pneumonitis.

Additionally, the tangent fields primarily extend superiorly rather than deeper into the chest, meaning the heart should be similarly spared as when treating the breast alone. I would argue that the dose should be the same, regardless of whether you’re covering level 1-2 axilla vs just the whole breast. We also have several effective heart-sparing techniques, such as prone positioning or breath-hold, which further mitigate heart dose.

In the event of an isolated, pathologically confirmed axillary recurrence following SLNB omission, what is your preferred salvage strategy?

Once an isolated axillary recurrence is pathologically confirmed, we would first complete thorough staging to rule out disease elsewhere. If the recurrence is isolated to the axilla, management returns to multidisciplinary discussion, considering factors such as receptor status of the nodes and resectability. We ask our medical and surgical oncology colleagues if chemotherapy is now indicated before surgery.

My preferred approach for isolated axillary recurrences would be to evaluate the role of chemotherapy upfront, followed by surgery if it’s amenable. Subsequently, we typically recommend radiation with a supraclavicular field, potentially foregoing re-irradiation to the breast or chest wall. Matching fields carefully is essential to minimize overlap with previous whole breast treatment. This scenario highlights an important consideration regarding the use of the high tangents initially: one critical organ at risk at the junction of prior and new fields is the brachial plexus. As radiation oncologists, we must be cautious about brachial plexopathy, a debilitating [adverse] effect characterized by numbness, tingling, or weakness resulting from excessive cumulative dose tolerance. I emphasize to residents, when using high tangents, carefully assess the brachial plexus dose. If a recurrence develops just superior to previously treated high tangents, where you initially opted against a dedicated supraclavicular field, matching fields safely becomes challenging due to the pre-existing high dose, increasing the risk to the brachial plexus. If, however, the initial treatment was limited to the breast, consistent with clinical trial approaches (Z0011, SOUND, INSEMA), this issue is largely avoided.

Is there anything else you would like to highlight today?

Another point I would like to discuss regarding high tangents, one reason they became popular in the US 5 or more years ago is that they allowed moderately hypofractionation of the radiation course. Historically, if regional nodal irradiation was indicated, they generally gave 5 to 6 weeks of radiation was typically recommended. At that time, data supporting shorter, 3-4 week regimens were still emerging. Currently, the data from studies such as RT CHARM [NCT03414970], along with recent American Society for Radiation Oncology [ASTRO] guidelines, there is now support 15 to 16-day courses even when nodes are included. Originally, one benefit of high tangents was completing radiation sooner because nodal coverage was omitted. However, now that both breast and nodal treatments share the same short schedule, this specific advantage is less compelling.

Additionally, there are technical variations in treating the nodes internationally. For example, not all institutions routinely include the internal mammary nodes when treating the nodes, avoiding deep tangents into the chest. For supraclavicular fields, delineation guidelines vary: The Radiation Therapy Oncology Group (RTOG) superior field extents to the cricoid cartilage. The ESTRO guidelines for early breast cancer recommend coverage only up to the subclavian artery arch, often sparing a significant portion of the thyroid gland. Radiation oncologists might consider a balanced approach for patients with limited node involvement, choosing field designs that maximally spare the lung, heart, and thyroid, while still adequately covering the highest risk echelon of nodal drainage in the level 1-4 axilla.

Prospective trials assessing management of limited nodal disease (micrometastases, 1-3 nodes positive) are generally limited and vary widely in practice. The ongoing phase 3 MA.39 trial [NCT03488693; also known as TAILOR RT] is testing the utility of regional nodal irradiation vs whole breast alone for patients with limited nodal disease, for those with low-risk Oncotype scores (<18). Until these results are available, decisions should remain individualized, involving multidisciplinary input (medical, surgical, and radiation oncologists), recognizing that existing data supporting regional nodal irradiation for N1 disease is robust. To me, MA.39 is a special trial, considering the true equipoise we have regarding nodal irradiation for this subset of patients.

References

1. Gentilini OD, Botteri E, Sangalli C, et al. Sentinel lymph node biopsy vs no axillary surgery in patients with small breast cancer and negative results on ultrasonography of axillary lymph nodes: The SOUND randomized clinical trial. JAMA Oncol. 2023;9(11):1557-1564. doi:10.1001/jamaoncol.2023.3759
2. Reimer T, Stachs A, Veselinovic K, et al. Axillary surgery in breast cancer - primary results of the INSEMA Trial. N Engl J Med. 2025;392(11):1051-1064. doi:10.1056/NEJMoa2412063

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