1. Perron, Michelle

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Some young women with breast cancer who achieve a pathologic complete response (pCR) after neoadjuvant chemotherapy might be better served by standard radiotherapy treatment rather than de-escalated care, as a recent study suggests.


The retrospective review of 155 breast cancer patients ages 40 years and younger found that women who achieved a pathologic response in the lymph nodes (LNs) but had residual disease in the breast had outcomes similar to patients who remained LN-positive. Until further research is available, "our group thinks the oncology community should be cautious about de-escalating therapy in women under the age of 40 who do not achieve a pCR in both the nodes and the breast," said Kathleen Horst, MD, Associate Professor of Radiation Oncology at the Stanford Cancer Institute. She was the senior author of the study, published in a recent issue of the Journal of the National Comprehensive Cancer Network (2018;16(7):845-850).


Two areas of interest led the researchers to undertake this study, Horst told Oncology Times. First, the Stanford group has a particular interest in locoregional outcomes, in addition to disease-free and overall survival outcomes, in young women with breast cancer. "The study was designed to look at women diagnosed with breast cancer under the age of 40 and to try to characterize the types of recurrences in order to better understand which young patients might benefit from escalation of treatment and which may be candidates for de-escalation," Horst explained.


The second influence was an ongoing trial (NSABP B-51/RTOG 1304) that is evaluating the role of radiotherapy in women with node-positive disease who achieve a pCR in the nodes after neoadjuvant chemotherapy (NAC).


"In this trial, if women undergo breast-conserving surgery, they are randomized to either whole breast radiotherapy alone or whole breast radiotherapy and regional nodal irradiation," Horst said. "If they undergo mastectomy, they are randomized to postmastectomy radiotherapy or no radiotherapy. The inclusion criteria allow patients who have achieved a pCR in the nodes regardless of the response in the breast. So, we were particularly interested in looking at this group of patients to see whether the response in the breast impacted outcomes."


Study Methods

This single-institution analysis focused on women diagnosed with breast cancer at age 40 years or younger and who were treated at Stanford between 1991 and 2015. A total of 155 patients were identified; 40 were diagnosed and treated between 1991 and 2004, and 115 were diagnosed and treated between 2005 and 2015. All patients received NAC and surgery with or without radiation. Patients whose surgical or radiologic records were not available at the time of analysis were excluded from the retrospective analysis. Patients with metastatic disease at the time of diagnosis or who received chemotherapy for another cancer diagnosis were also excluded.


In this analysis, pCR was defined as no evidence of residual invasive tumor in the breast or in the breast and sampled axillary LNs. Patients were considered to have partial response if their LNs showed no tumor but residual tumor was found in the breast, or if they had no breast tumor but had residual tumor in the LNs. Patients who had residual tumor in both the breast and the LNs were classified as having a limited response. Residual cancer burden was not routinely assessed in all pathology samples; therefore, it was not included.


Statistical analysis was performed using clinical and pathologic information available for all patients. This included clinical stage at diagnosis, hormone receptor status, HER2 status, Ki67 percentage, BRCA1/2 mutation status, type of NAC, use of HER2-targeted therapy and hormonal therapy, size of residual disease, LN involvement, presence of lymphovascular invasion, and achievement of pCR. Local, regional, and distant failure were recorded for each patient.


Study Results

The median age of the 155 patients included in the review was 36 years. The median follow-up time was 52 months. All patients received NAC followed by mastectomy or lumpectomy. One hundred thirty-two received adjuvant radiotherapy. Forty-two of 47 patients received radiation after lumpectomy (five refused), and 90 of 108 received radiation after mastectomy (18 refused).


Thirty-nine patients (25.2%) achieved pCR after NAC, and 59 patients (38.1%) had residual disease in both the breast and the LNs; 36.7 percent of patients achieved a degree of pathologic response but not pCR.


"Similar to other studies, we found that patients who achieved a pCR in the nodes and breast did well," Horst said. "However, we were surprised to find that those who achieved a pCR in the nodes but still had residual disease in the breast did poorly, similar to those who had residual disease in the nodes. This was a surprise because some data suggest that residual disease in the nodes, rather than the breast itself, is the most important prognostic factor."


This analysis is believed to be the first to evaluate pathologic nodal response and outcomes among women <=40 years who were treated with NAC. "We focused on young women treated with NAC because this population is infrequently studied on its own, yet has worse survival compared with older women despite higher rates of pCR," the authors wrote. "... Our analysis reveals that women <=40 years with residual disease in the breast or LNs have increased locoregional recurrence (LRR) rates compared with those who achieve pCR in both the breast and LNs.


"Perhaps the most compelling finding of our analysis is that women with residual disease in the breast, despite having a pCR in the LNs, had similar LRR rates as those with residual nodal disease," the authors continued. "This important finding suggests that omitting radiation therapy in patients with any residual disease after NAC, whether in the breast alone or in the breast and LNs, should be considered with caution."


The ongoing NSABP B-51/RTOG 1304 study will provide more information about the role of regional nodal irradiation and postmastectomy radiotherapy in patients who achieve a pCR in the nodes but have residual disease in the breast, Horst noted. In the meantime, she and her colleagues urge caution about de-escalation of therapy in young women diagnosed with breast cancer.


"While many women with breast cancer understandably want to avoid radiotherapy, it will be important to follow up on the randomized data in order to confirm or refute the impact of radiotherapy not only on LRR, but also on distant recurrences," she said.


Michelle Perron is a contributing writer.