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ABSTRACT & COMMENTARY
Synopsis: The cytologic responses in breast cancers during the 96 hours following the first dose of a preoperative (neoadjuvant) paclitaxel chemotherapy regimen were evaluated in a pilot study using serial fine-needle aspirations (FNAs). Eleven women receiving neoadjuvant chemotherapy with paclitaxel (200 mg/m2 every 2 weeks for a total 4 cycles) for primary breast cancer of at least 2 cm in greatest diameter received serial FNAs before treatment and at 24, 48, 72, and 96 hours after the first paclitaxel dose. Apoptotic and mitotic indices were determined in breast cancer cells from the FNA samples, and the cumulative apoptotic response during the first 96 hours after the first dose of paxlitaxel had an almost linear relationship with the extent of tumor reduction. Serial FNAs provide a minimally invasive strategy to evaluate in vivo cellular responses to chemotherapy and may allow for development of chemopredictive assays.
Source: Symmans WF, et al. Clin Can Res 2000;6: 4610-4617.
Neoadjuvant chemotherapy is given to women with locally advanced primary breast cancer to reduce tumor size for subsequent surgical management and to predict patient outcome based on the observed preoperative chemotherapy response.1,2 Use of neoadjuvant chemotherapy can result in a pathologic complete response (pCR) of invasive breast cancer in the breast and axillary lymph nodes, and patients with a pCR have improved disease-free survival compared with patients who fail to achieve this outcome.3 Conventional measures of treatment response, such as physical exam, mammography, and breast sonography, have not been able to accurately and consistently predict pathologic response to treatment.4-6 Thus, a predictive biomarker of treatment response could be useful for the management of these patients.
Symmans and colleagues report results of a pilot study involving 11 patients with primary breast cancer without evidence of systemic metastases and a breast tumor of at least 2 cm. The patients received neoadjuvant paclitaxel chemotherapy (200 mg/m2 every 2 weeks for a total of 4 cycles) and monitoring that included a baseline FNA as well as serial FNAs 24, 48, 72, and 96 hours after the first paclitaxel infusion. Clinical and radiological measurements of the primary breast tumor were made prior to paclitaxel as well as preoperatively following the fourth cycle of paclitaxel. The cellular samples from the FNAs were fixed in 95% ethanol and stained with H&E. Apoptotic cells were identified following staining with H&E, and an apoptotic and mitotic index were determined at each timepoint. The background heterogeneity of these measurements was shown by analysis of apoptotic and mitotic indices in a separate group of seven untreated resected invasive breast cancers.
Patients received an initial FNA prior to receiving paclitaxel neoadjuvant therapy. The apoptotic and mitotic indices in these baseline samples did not correlate with the proportion of residual tumor following treatment. Patients then received FNAs 24, 48, 72, and 96 hours after the first paclitaxel infusion. The apoptotic response to the first dose of paclitaxel did correlate with the proportion of residual cancer following the neoadjuvant treatment. This inverse correlation of relative change in apoptotic index (compared with the pretreatment index) with residual cancer volume occurred at each of the four timepoints after the first paclitaxel dose and was even greater when a cumulative apoptotic response was calculated for days 1-4. No correlation was present between the cumulative mitotic response and the proportion of residual cancer after the neoadjuvant paclitaxel therapy. Symmans et al conclude that larger clinical studies are indicated to validate use of the apoptotic response as a predictive biomarker for breast cancer tumor response to paclitaxel neoadjuvant therapy.
Comment by Mark R. Albertini, MD
Paclitaxel is a taxane with demonstrated activity against breast cancer.7 A preclinical murine model of paclitaxel therapy identified peak apoptotic index and pretreatment apoptotic index as it correlates with murine tumor reduction.8 A similar predictive biomarker for breast cancer response to paclitaxel neoadjuvant therapy could be clinically useful for management of patients with locally advanced breast cancer. Symmans et al proceeded with the current study to determine potential use of serial FNA to determine apoptotic response as a guide for treatment of patients receiving paclitaxel neoadjuvant therapy. Results from this small pilot study demonstrate feasibility of this approach and suggest that meaningful biologic data can be obtained with this minimally invasive procedure.
The apoptotic response to a single dose of paclitaxel lasted for about four days in patients treated on this study. The potential relevance of this observation for decisions about paclitaxel scheduling requires clinical investigation. The cumulative apoptotic response during the initial 96 hours following the first dose of paclitaxel had an almost linear relationship with tumor reduction. While this observation requires confirmation in a larger study, the possibility exists for an early biomarker for antitumor response in these patients. Thus, decisions about timing of surgery or changes in chemotherapy regimens may be possible earlier in the course of the patient’s treatment. Patients without a significant apoptotic response to an initial dose of paclitaxel could be identified as candidates for alternate neoadjuvant strategies or earlier surgical intervention.
The use of FNA monitoring of tumor cells during therapy may allow for investigation of resistance mechanisms to treatment as well as to identify predictive biomarkers of tumor response. This approach is minimally invasive and offers the possibility of increasing our knowledge of breast cancer cellular responses during therapy. While monitoring apoptosis may or may not be confirmed as a predictive biomarker for paclitaxel neoadjuvant therapy, this FNA monitoring strategy merits further clinical investigation in this as well as additional clinical settings.
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