Liquid biopsy may improve presurgical assessment of locally advanced breast cancer
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Plasma cell-free DNA integrity assessed prior to surgery accurately predicted achievement of pathologic complete response to neoadjuvant chemotherapy among patients with locally advanced breast cancer, according to study results.
The findings, presented at the virtual American Association for Cancer Research Annual Meeting, also showed potential for combining this liquid biopsy approach with MRI to improve prediction of pathologic complete response in this group.
After receiving neoadjuvant chemotherapy, patients with locally advanced breast cancer are assessed for response to guide the appropriate course of surgery. MRI typically is used for this assessment, despite its “suboptimal accuracy,” Francesco Ravera, MD, PhD, fellow in the department of internal medicine at University of Genoa in Italy, told Healio.
“This impacts the surgical management of patients affected by breast cancer, in particular regarding lymph node disease assessment,” he said. “Whereas patients presenting with residual disease in lymph nodes at radiology directly undergo extensive axillary dissection, complete responders require sentinel lymph node biopsy. An accurate way to effectively assess the achievement of pathologic complete response to the systemic treatment may allow us to spare complete responders from sentinel lymph node biopsy, avoiding their exposure to possible side effects of this procedure.”
Ravera and colleagues evaluated whether an electrophoresis-based method for assessment of plasma cell-free DNA integrity could be used to evaluate response to neoadjuvant chemotherapy among patients with breast cancer.
The analysis included data of 62 patients undergoing anthracycline- or taxane-based neoadjuvant chemotherapy followed by surgery. Researchers collected plasma samples from the patients at diagnosis, after anthracycline administration and after completion of neoadjuvant chemotherapy but prior to surgery.
Researchers evaluated the plasma samples for integrity of cell-free DNA based on the knowledge that low cell-free DNA integrity, which corresponds to high cell-free DNA fragmentation, is associated with neoplasms. They used automated electrophoresis (2200 TapeStation, Agilent) to characterize the concentration of the cell-free DNA fragments as 90 base pairs (bp) to 150 bp, 150 bp to 220 bp, 221 bp to 320 bp, 100 bp to 300 bp and 321 bp to 1,000 bp.
Researchers conducted cell-free DNA fragmentation profiling on samples taken after completion of neoadjuvant chemotherapy from 38 patients, which they matched with results of postsurgical histopathological examinations.
Eleven of 38 patients experienced pathologic complete response to neoadjuvant chemotherapy, whereas the other 27 had an incomplete response with evidence of residual disease in the breast or axillary nodes, for a 30/70 ratio of response to nonresponse.
Researchers selected a normalized measure of cell-free DNA integrity — expressed as a ratio of the concentration of 321 bp to 1,000 bp sized fragments to the concentration of 150 bp to 200 bp sized fragments — that appeared most predictive of response to neoadjuvant chemotherapy.
Researchers used this ratio to form the cell-free DNA integrity index — for which values of 2.71 or greater were associated with the achievement of pathologic complete response, whereas values less than 2.71 were associated with incomplete response — which they used to build an explorative classifier to predict response. Through bootstrapped logistic regression, they compared the performance of this classifier with MRI in predicting response to neoadjuvant chemotherapy.
MRI demonstrated an accuracy of 77.1% in predicting pathologic complete response, with a sensitivity of 72.7% and specificity of 81.5%, whereas the cell-free DNA integrity index showed an accuracy of 81.6%, a sensitivity of 81.8% and specificity of 81.5%.
When combining MRI with the cell-free DNA integrity index, in cases where the techniques were concordant, overall accuracy increased to 92.6%, with a positive predictive value of 87.5% and a negative predictive value of 94.7%.
These data show “great potential” in the use of cell-free DNA integrity to assess response to neoadjuvant chemotherapy, but the study is limited by its small sample size, according to Ravera.
“Sample size expansion is required to assess the effective accuracy of cell-free DNA integrity and its combination with MRI in the prediction of the response to systemic treatment,” he told Healio. “Moreover, the study of the biological bases underlying the alteration of cell-free DNA integrity in neoplastic patients would be of interest, possibly having implications for other clinical purposes.”
Perspective
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Kristen Whitaker, MD, MS
Neoadjuvant chemotherapy (NAC) is used increasingly for patients with certain types of breast cancer, such as triple-negative and HER2-positive disease. Assessing a patient’s response to NAC prior to surgery helps guide surgical management regarding appropriate axillary node evaluation and may in the future be critical for determining whether a patient can forgo surgery altogether based on her response to chemotherapy, a strategy actively being investigated.
Although various imaging modalities, such as mammography, ultrasound, PET/CT or MRI can be used to assess response to neoadjuvant chemotherapy, breast MRI is typically considered the most accurate as it correlates best with pathologic breast tumor size. With this said, MRI is an imperfect test for predicting pathologic complete response(pCR) after NAC, with most studies demonstrating that breast MRI has only about an 80% accuracy for predicting pCR in this setting. In addition, obtaining MRI for evaluation of response to NAC may be difficult for some patients due to claustrophobia and issues of cost or proximity to centers with MRI availability. Thus, developing a tool that can be used in addition to or in place of MRI to predict response to NAC is exciting and much needed.
Based on the findings of Ravera and colleagues, using liquid biopsy to examine cell-free DNA integrity may hold promise for evaluating response to NAC in patients with breast cancer. Researchers found that cell-free DNA was slightly more accurate than MRI at predicting pCR in patients after NAC (81.6% vs. 77.1%) and that the combined prediction of pCR was highest when researchers used both MRI and cell-free DNA integrity index.
Although the sample size of this study was small, if these findings are validated in larger samples, the use of liquid biopsy in addition to MRI to predict pCR could become a standard of care given that blood can be collected easily for the cell-free DNA analysis and this step can be added easily to the clinical flow.
Ideally, liquid biopsy would be most useful for predicting pCR after NAC if future, larger studies demonstrate that liquid biopsy alone is more accurate than MRI for predicting pCR. This would mean that, in the future, it may be possible to eliminate the use of breast MRI after NAC and instead replace it with liquid biopsy to circumvent some of the issues associated with completing MRI noted above and ultimately to provide cost-conscious yet high-quality care to our patients.
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Cirmena G, et al. Abstract LB063. Presented at: American Association for Cancer Research Annual Meeting (virtual meeting); April 10-15, 2021.
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