Findings may help resolve ‘active debate’ about adjuvant radiotherapy for breast cancer
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SAN ANTONIO — Treatment de-escalation may be possible for patients with breast cancer who respond well to neoadjuvant chemotherapy, according to randomized phase 3 study results presented at San Antonio Breast Cancer Symposium.
Among patients whose breast cancer converted from lymph node-positive to lymph node-negative after neoadjuvant chemotherapy, those who skipped adjuvant regional nodal irradiation (RNI) exhibited no elevated risk for recurrence or death 5 years after surgery.
The findings help provide clarity to an “active debate” about optimal postsurgical treatment for patients who present with axillary node involvement, receive neoadjuvant chemotherapy and are found to be pathologically node negative at surgery, according to researcher Eleftherios “Terry” Mamounas, MD, MPH, professor of surgery at University of Central Florida, medical director of the comprehensive breast program at Orlando Health Cancer Institute and chair of NRG Oncology Breast Committee.
“I think the clinical community certainly will embrace these results and take them into consideration for appropriate patients,” Mamounas told Healio. “These findings also will prompt conversations between clinicians and patients, who will start asking about this approach. I’ve had requests already from patients who knew these data were going to be presented, because they’re really looking to avoid radiotherapy.”
Background
Neoadjuvant chemotherapy may be offered to patients diagnosed with breast cancer that has spread to regional lymph nodes.
No standard postsurgical treatment approach has been established for patients whose lymph nodes become cancer free after neoadjuvant therapy.
If they are considered to have lymph node-positive disease — as they presented at diagnosis — recommended treatment includes chest wall irradiation plus adjuvant RNI after mastectomy, or whole breast irradiation plus RNI after breast-conserving surgery.
If patients are considered to have lymph node-negative disease — how they present at time of surgery — they would be eligible to forgo adjuvant RNI. Doing so could help patients avoid complications such as fatigue, pain and lymphedema, as well as potential negative effects on breast reconstruction.
Consequently, it is important to explore whether RNI can be safely omitted for these patients, Mamounas said.
Methods
The NRG Oncology/NSABP B-51/RTOG 1304 trial included 1,641 patients with lymph node-positive, nonmetastatic breast cancer who completed at least 8 weeks of neoadjuvant chemotherapy and underwent either mastectomy or breast-conserving surgery.
All patients subsequently were determined to have lymph node-negative disease per sentinel node biopsy, axillary lymph node dissection or both.
Researchers randomly assigned half of patients to chest wall irradiation plus RNI after mastectomy, or whole breast irradiation plus RNI after breast-conserving surgery.
The other half received no RNI, instead undergoing observation after mastectomy or whole breast irradiation after breast-conserving surgery.
Invasive breast cancer recurrence-free interval served as the primary endpoint. Secondary endpoints included locoregional recurrence-free interval, distant recurrence-free interval, DFS and OS.
Study protocol specified the final analysis would take place after 172 events or 10 years after study initiation.
At SABCS, Mamounas presented the time-driven analysis, which included 1,556 evaluable patients (median age, 52 years; range, 21-84; 69% white). More than half (56%) had HER2-positive disease, 23% had triple-negative disease, and 21% had hormone receptor-positive/HER2-negative disease.
Median follow-up was 59.5 months (interquartile range, 40.7-74.1).
Key findings
Results showed a comparable percentage of patients in each group remained free of invasive breast cancer recurrence 5 years after surgery (91.8% for no RNI vs. 92.7% for RNI; HR = 0.88; 95% CI, 0.6-1.29).
Similar percentages of patients in each group remained alive (94% vs. 93.6%; HR = 1.12; 95% CI, 0.75-1.68), free of disease recurrence (88.5% vs. 88.3%; HR = 1.06; 95% CI, 0.79-1.44), free from distant recurrence (93.4% for each group; HR = 1; 95A% CI, 0.67-1.51) and free from isolated loco-regional recurrence (98.4% vs. 99.3%; HR = 0.37; 95% CI, 0.12-1.16) 5 years after surgery.
No study-related deaths occurred, and researchers reported low rates of grade 4 toxicity (0.1% for no RNI vs. 0.5% for RNI). A slightly higher percentage of patients who received RNI developed grade 3 toxicity (10% vs. 6.5%), the most common of which was radiation dermatitis.
Mamounas and colleagues acknowledged a potential study limitation in that patients experienced fewer breast cancer recurrences than anticipated. This affected investigators’ ability to conduct planned statistical analyses based on number of recurrences.
Researchers will continue to follow patients to glean more data about long-term outcomes.
However, findings suggest downstaging cancer-positive regional lymph nodes with neoadjuvant chemotherapy can allow some patients to skip adjuvant RNI without compromising oncologic outcomes, Mamounas said.
“Treatment de-escalation is not just an opportunity. It’s a mandate because we keep adding so many treatments for patients,” Mamounas told Healio. “We need to pursue studies that examine de-escalation, but we have to pursue them judiciously in settings where we have some data to suggest a group of patients will do OK without the extra treatment. And as our systemic therapies continue to get better, it allows us to de-escalate locoregional therapy much easier, so it’s clearly a very important strategy.”
Perspective
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All patients in this trial had to have achieved pathologic complete response (pCR) to neoadjuvant chemotherapy. The trial assessed whether patients who presented with bulky disease but had a pCR in the nodes and breast after neoadjuvant still needed radiation. We’ve always felt they do, but we’ve been basing it on the original tumor, not on what was left.
This was a very well-powered trial, enrolling more than 1,600 women who reflected the U.S. population.
Findings showed reginal nodal radiation made no difference with regard to locoregional recurrence. There were few recurrences overall and, in an era of effective systemic therapy, that’s not a surprise. Results also showed no difference in disease-free interval, DFS or OS.
One challenge we’ve traditionally had is that a lot of patients want immediate reconstruction. We’d say, “Well, you have a 5-cenitmeter tumor, you have a lymph node involved, you have stage III disease, let’s wait because you’ll probably need radiation and that could compromise the cosmetic outcome.” Now we see that if a patient achieves a pCR, maybe that person can plan to have immediate reconstruction after mastectomy and not worry about having chest wall radiation.
This does beg the question of whether we can de-escalate radiation for a subset of people who respond well to neoadjuvant chemotherapy, and that’s a very good thing.
The trial that really led to broad discussion of minimal residual disease (MRD) testing in oncology examined the role of adjuvant chemotherapy for patients with stage II colon cancer. Those who were MRD negative received nothing and those who were MRD positive received chemotherapy. The results — published in The New England Journal of Medicine — showed no difference in outcomes. We need to think about doing more of those types of trials in breast cancer, and I believe MRD can play a role when we think about the theme of therapy de-escalation.
Perspective
Back to TopKamran A. Ahmed, MD
There is ongoing debate about how to manage patients who initially present with clinically node-positive disease but then convert to pathologically node-negative following neoadjuvant chemotherapy with regard to receipt — and extent — of radiation therapy to the regional lymph nodes.
We have had some data from RAPCHEM — a Dutch prospective registry study — as well as a secondary analysis of the B18/B27 study, and those data showed patients who convert to pathologically node-negative following receipt of neoadjuvant chemotherapy in the clinical N1 setting are at low risk for locoregional recurrence, such that potential de-escalation of radiation therapy might be possible. The 5-year data we’re seeing from the B-51 trial suggest this continues to be the case and that de-escalation of radiation therapy fields might be possible for these patients.
We continue to learn more about the biology of breast cancer and how our treatment paradigms can no longer follow a one-size-fits-all approach. I certainly am encouraged by the results thus far at the 5-year time point, and the data are important to have to counsel patients who meet study eligibility and convert to pathologically node negative on the potential for tailoring radiation therapy based on their response to neoadjuvant chemotherapy. We await the long-term 10-year data, but these initial 5-year results are certainly intriguing.
Perspective
Back to TopKate Lathrop, MD
The results of this study were very eagerly awaited. This has been an open-ended question and, in tumor boards, we didn’t have the data to make decisions about whether these patients would benefit from radiation therapy after pathologic complete response to neoadjuvant therapy.
We’re using so much more neoadjuvant therapy, and those regimens are getting better as we develop more targeted therapies, so this is a very poignant question. It’s a very important for patients, too, because we don’t want to subject them to additional toxicity, costs and time to come in for their therapies. Knowing that these patients did just as well without radiation makes this a big study, and I think it’s going to change a lot of opinions about how much radiation we can avoid for our patients.
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Mamounas E, et al. Abstract GS02-07. Presented at: San Antonio Breast Cancer Symposium; Dec. 5-9, 2023; San Antonio.
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