Neoadjuvant Chemotherapy Has Led to De-Escalation of Breast Cancer Surgery and Radiation

Neoadjuvant chemotherapy has been instrumental in surgical de-escalation for the breast and axilla across breast cancer subtypes, according to Terry P. Mamounas, MD, MPH, FACS, who added that axillary lymph node response to neoadjuvant chemotherapy is an oncologically safe way to decide whether to de-escalate regional nodal radiotherapy.

“For patients with triple-negative [breast cancer (TNBC)] or HER2-positive breast cancer, by individualizing post-neoadjuvant systemic therapy based on pathologic complete response [pCR], outcomes can be improved over the traditional adjuvant [treatment] approaches,” Mamounas said in a presentation during the 41st Annual Miami Breast Cancer Conference.¹

In his presentation, Mamounas highlighted historical achievements with neoadjuvant chemotherapy in breast cancer, advancements in locoregional therapy after neoadjuvant chemotherapy, and how the efficacy of neoadjuvant chemotherapy has influenced axillary surgery decisions and continues to drive developments in this arena.

Mamounas is the medical director of the Comprehensive Breast Program at Orlando Health Cancer Institute in Florida, as well as a professor of surgery at the University of Central Florida College of Medicine and a clinical professor of clinical sciences at Florida State University College of Medicine in Tallahassee.

Making a Case for Neoadjuvant Chemotherapy

Mamounas began the presentation with an overview of the evolution of the role of neoadjuvant chemotherapy for patients with breast cancer. He noted that this treatment method was originally used to convert patients with inoperable, locally advanced breast cancer to surgical candidates, highlighting that clinical research supported the use of neoadjuvant chemotherapy as a suitable alternative to adjuvant chemotherapy for patients with large, operable breast cancer and may provide clinical advantages over adjuvant chemotherapy in certain patients.

Accordingly, Mamounas emphasized the importance of achieving pCR with neoadjuvant chemotherapy, which is associated with improved outcomes vs patients who do not achieve pCR in this setting. Notably, pCR is a surrogate end point for neoadjuvant chemotherapy efficacy, and in 2013, the FDA classified pCR as an acceptable end point to support the accelerated approval of new neoadjuvant breast cancer agents.² Mamounas noted that across several breast cancer clinical trials, drugs that improved pCR rates also improved disease-free survival (DFS) and overall survival (OS) rates in HER2-positive breast cancer and TNBC.¹

“In medical oncology, [neoadjuvant chemotherapy] has improved pCR outcomes,” he said. “Can we capitalize on these improvements?”

Mamounas listed several ways that precision medicine might be leveraged to maximize the clinical effects of neoadjuvant chemotherapy. He explained that better predictors of pCR need to be identified, including baseline biomarkers and early biomarker changes that may occur with the use of neoadjuvant chemotherapy. He emphasized the continued benefits of using pCR and event-free survival as end points to support accelerated drug approvals. He also highlighted the importance of using primary tumor response to guide personalized locoregional and systemic therapy decisions.

Taking an Individualized Approach to Neoadjuvant Chemotherapy Response

Traditionally, locoregional neoadjuvant chemotherapy has been used to make mastectomy candidates eligible for breast-conserving surgery and has improved cosmesis by reducing the lumpectomy size in patients with large tumors who are eligible for breast conservation, Mamounas elaborated.

“The challenge…is to figure out how the tumor shrinks in response to neoadjuvant chemotherapy,” he explained. “We know that some tumors shrink concentrically…but some others thin out, but then there still are residual tumor cells…in the same area.”

Mamounas emphasized how determining the extent of the residual tumor and identifying individual patients’ tumor shrinkage patterns, such as through tumor subtyping and breast imaging, can guide lumpectomy decisions. However, he also advocated for the continued use of surgery in patients who undergo neoadjuvant chemotherapy.

A 2018 Early Breast Cancer Trialists' Collaborative Group meta-analysis evaluating rates of locoregional recurrence with neoadjuvant vs adjuvant chemotherapy according to surgery use demonstrated lower 10-year recurrence rates in patient populations that commonly received surgery (n = 4094) vs those that received surgery less commonly (n = 662), at 15.1% vs 33.7%, respectively, in patients who received neoadjuvant chemotherapy.³ These rates were 11.9% and 20.4%, respectively, in those who received adjuvant chemotherapy.

“There is a slight increase in locoregional recurrence with neoadjuvant chemotherapy vs adjuvant chemotherapy, but that’s probably because we downstage these tumors to [be eligible for] lumpectomy, so biologically, these would have higher rates of recurrence,” Mamounas contextualized.¹ “Some trials at the time did not do surgery when the patients had a clinical CR; they just gave radiation. Those trials have shown significantly higher [locoregional recurrence rates], so surgery is still important.”

Identifying Axillary Surgery Trends and Trajectories

Mamounas pivoted to spotlight another example of tailored locoregional neoadjuvant chemotherapy, which involves reducing the extent of axillary surgery by downstaging involved axillary nodes through sentinel lymph node biopsy (SLNB). He also noted how the extent of locoregional radiotherapy may be reduced through the downstaging of primary tumors and axillary nodes per biopsy results and mentioned the potential for eliminating all forms of locoregional therapy either by using more active therapies and/or selecting patients more appropriately through the use of imaging and biomarkers.

“We know that neoadjuvant chemotherapy downstages axillary metastases,” Mamounas said, drawing upon findings from early randomized clinical trials comparing neoadjuvant chemotherapy with surgery-first approaches, which showed that neoadjuvant chemotherapy downstaged axillary nodes in approximately 30% to 40% of patients, and that axillary downstaging of 50% to 75% was expected with this treatment approach in patients with TNBC or HER2-positive disease.

“There was a lot of debate [about whether] to do SLNB before or after,” Mamounas explained. “After long debate, it is best to do it after so you can capitalize on the downstaging effect of neoadjuvant chemotherapy.”

However, he noted that questions remained regarding the safety of SLNB after neoadjuvant chemotherapy in patients with positive axillary nodes. Four prospective clinical trials evaluated this area of uncertainty, all of which found that overall false-negative rates were between 8.4% and 14.2%. Although Mamounas noted that these rates were higher than anticipated, he explained that all the trials also demonstrated that false negative rates decreased upon continued node removal.

Furthermore, a study conducted at The University of Texas MD Anderson Cancer Center in Houston evaluated false-negative rates in patients with positive nodes who underwent SLNB to detail the nodal basin status in all-comers receiving neoadjuvant chemotherapy.4 In only the clipped nodes, the false negative rate was 4.2% (95% CI, 1.4%-9.5%). In the sentinel lymph nodes overall, this rate was 10.1% (95% CI, 4.2%-19.8%), and in both the sentinel lymph nodes and the clipped nodes, this rate was 1.4% (95% CI, 0.03%-7.3%). These findings were validated in the prospective RISAS trial (NCT02800317), in which radioactive iodine seed placement in the axilla elicited a false-negative rate of 3.5% (CI, 1.38%-7.16%) in patients with breast cancer who received SLNB after neoadjuvant chemotherapy.⁵

“It’s not only recurrence in the axilla that we’re worried about; it’s also making the right decision for the patient to get appropriate adjuvant therapy,” Mamounas emphasized.¹ “There is a lot of effective therapy now…for patients who have residual disease, so you don’t want to miss those.”

Across several studies, rates of positivity outside of the sentinel lymph nodes remain high in patients with positive sentinel lymph nodes after neoadjuvant chemotherapy, ranging from 61% to 71.5%, Mamounas elaborated, who noted that the standard of care for these patients is axillary lymph node dissection. Moreover, researchers have asked whether reduction of regional nodal radiotherapy is possible in patients with cN+ disease and evaluated the feasibility of using neoadjuvant chemotherapy to convert these patients to ypN0 disease.

Findings from the phase 3 NRG/NSABP B-51/RTOG 1304 trial (NCT01872975), which evaluated if the addition of regional nodal irradiation to breast radiation significantly improves invasive breast cancer recurrence-free survival (RFS), were presented at the 2023 San Antonio Breast Cancer Symposium.⁶ At a median follow-up of 59.5 months (interquartile range, 40.7-74.1), the estimated 5-year invasive breast cancer RFS rate was 92.7% in patients who received regional nodal irradiation vs 91.8% in those who did not (HR, 0.88; 95% CI, 0.60-1.29; P = .51).

Furthermore, little difference was seen between the regional nodal irradiation and non–regional nodal irradiation arms regarding isolated loco-regional RFS, distant recurrence-free interval, DFS, and OS. Additionally, a planned subset analysis demonstrated no significant interaction on the effects of radiotherapy between the 2 arms when patients were stratified by factors such as type of surgery, estrogen receptor (ER) status, HER2 status, pCR status, and adjuvant chemotherapy status. Moreover, an exploratory subgroup analysis evaluating invasive breast cancer RFS rates with and without regional nodal irradiation showed that the only significant difference between the arms occurred when patients were stratified by tumor subtype, in which patients with TNBC experienced improved outcomes with no regional nodal irradiation (HR, 2.30; 95% CI, 1.00-5.25; P = .037).

Overall, this trial showed that in patients with biopsy-proven axillary node involvement in whom neoadjuvant chemotherapy converted their axillary nodes to ypN0, regional nodal irradiation added to chest wall irradiation after mastectomy or whole-breast irradiation after lumpectomy did not improve 5-year outcomes.

“Neoadjuvant chemotherapy has allowed de-escalation of surgical therapy of the breast and the axilla,” Mamounas concluded.¹ “This de-escalation has occurred to a greater degree in TNBC and HER2-positive [breast cancer], but also in selected [patients with] ER-positive, HER2-negative [disease].”

References

1. Mamounas, T. New developments in loco-regional therapy after neoadjuvant chemotherapy. Presented at: 41st Annual Miami Breast Cancer Conference; March 7-10, 2024; Miami, Florida.
2. Pathological complete response in neoadjuvant treatment of high-risk early-stage breast cancer: use as an endpoint to support accelerated approval. Guidance for industry. FDA. July 2020. Accessed March 8, 2024. https://www.fda.gov/media/83507/download
3. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Long-term outcomes for neoadjuvant versus adjuvant chemotherapy in early breast cancer: meta-analysis of individual patient data from ten randomised trials. Lancet Oncol. 2018;19(1):27-39. doi:10.1016/S1470-2045(17)30777-5
4. Caudle AS, Yang WT, Krishnamurthy S, et al. Improved axillary evaluation following neoadjuvant therapy for patients with node-positive breast cancer using selective evaluation of clipped nodes: implementation of targeted axillary dissection. J Clin Oncol. 2016;34(10):1072-1078. doi:10.1200/JCO.2015.64.0094
5. Simons JM, van Nijnatten TJA, van der Pol CC, et al. Diagnostic accuracy of radioactive iodine seed placement in the axilla with sentinel lymph node biopsy after neoadjuvant chemotherapy in node-positive breast cancer. JAMA Surg. 2022;157(11):991-999. doi:10.1001/jamasurg.2022.3907
6. Mamounas E, Bandos H, White J, et al. Loco-regional irradiation in patients with biopsy-proven axillary node involvement at presentation who become pathologically node-negative after neoadjuvant chemotherapy: primary outcomes of NRG Oncology/NSABP B-51/RTOG 1304. Presented at: 2023 San Antonio Breast Cancer Symposium; December 5-9, 2023; San Antonio, Texas. GS02-07