Lee G. Wilke

Sentinel Lymph Node Surgery After Neoadjuvant Chemotherapy in Patients With Node-Positive Breast Cancer The ACOSOG Z1071 (Alliance) Clinical Trial

IMPORTANCE Sentinel lymph node (SLN) surgery provides reliable nodal staging information with less morbidity than axillary lymph node dissection (ALND) for patients with clinically node-negative (cN0) breast cancer. The application of SLN surgery for staging the axilla following chemotherapy for women who initially had node-positive cN1 breast cancer is unclear because of high false-negative results reported in previous studies. OBJECTIVE To determine the false-negative rate (FNR) for SLN surgery following chemotherapy in women initially presenting with biopsy-proven cN1 breast cancer. DESIGN, SETTING, AND PATIENTS The American College of Surgeons Oncology Group (ACOSOG) Z1071 trial enrolled women from 136 institutions from July 2009 to June 2011 who had clinical T0 through T4, N1 through N2, M0 breast cancer and received neoadjuvant chemotherapy. Following chemotherapy, patients underwent both SLN surgery and ALND. Sentinel lymph node surgery using both blue dye (isosulfan blue or methylene blue) and a radiolabeled colloid mapping agent was encouraged. MAIN OUTCOMES AND MEASURES The primary end point was the FNR of SLN surgery after chemotherapy in women who presented with cN1 disease. We evaluated the likelihood that the FNR in patients with 2 or more SLNs examined was greater than 10%, the rate expected for women undergoing SLN surgery who present with cN0 disease. RESULTS Seven hundred fifty-six women were enrolled in the study. Of 663 evaluable patients with cN1 disease, 649 underwent chemotherapy followed by both SLN surgery and ALND. An SLN could not be identified in 46 patients (7.1%). Only 1 SLN was excised in 78 patients (12.0%). Of the remaining 525 patients with 2 or more SLNs removed, no cancer was identified in the axillary lymph nodes of 215 patients, yielding a pathological complete nodal response of 41.0% (95% CI, 36.7%-45.3%). In 39 patients, cancer was not identified in the SLNs but was found in lymph nodes obtained with ALND, resulting in an FNR of 12.6% (90% Bayesian credible interval, 9.85%-16.05%). CONCLUSIONS AND RELEVANCE Among women with cN1 breast cancer receiving neoadjuvant chemotherapy who had 2 or more SLNs examined, the FNR was not found to be 10% or less. Given this FNR threshold, changes in approach and patient selection that result in greater sensitivity would be necessary to support the use of SLN surgery as an alternative to ALND. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00881361.

Cytotoxicity of Paclitaxel in Breast Cancer Is due to Chromosome Missegregation on Multipolar Spindles

The chemotherapy drug paclitaxel causes tumor regression and cell death by inducing high rates of chromosome missegregation on multipolar spindles. The Secret Life of Paclitaxel The classic chemotherapy drug paclitaxel is a standard part of treatment for breast cancer and other malignancies. Although it is commonly understood to act as a microtubule poison and lead to mitotic arrest, this knowledge is largely based on studies of cells in culture, with drug concentrations that may not be realistic. Now, Zasadil and coauthors measured the concentration of paclitaxel in real patients undergoing treatment with the drug, and then investigated the response of cancer cells to paclitaxel at these lower and more realistic concentrations. Unexpectedly, the cells treated under these conditions did not undergo mitotic arrest, but instead proceeded through mitosis with abnormal spindles, resulting in chromosome missegregation, which leads to tumor cell death. This intriguing discovery demonstrates that we may not know as much as we thought about the effects of one of our most common chemotherapy drugs. In addition, the findings from this study may lead to clinical applications both in optimizing the selection of chemotherapy drug combinations and in determining which patients are likely to respond to paclitaxel treatment. The blockbuster chemotherapy drug paclitaxel is widely presumed to cause cell death in tumors as a consequence of mitotic arrest, as it does at concentrations routinely used in cell culture. However, we determine here that paclitaxel levels in primary breast tumors are well below those required to elicit sustained mitotic arrest. Instead, cells in these lower concentrations of drug proceed through mitosis without substantial delay and divide their chromosomes on multipolar spindles, resulting in chromosome missegregation and cell death. Consistent with these cell culture data, most mitotic cells in primary human breast cancers contain multipolar spindles after paclitaxel treatment. Contrary to the previous hypothesis, we find that mitotic arrest is dispensable for tumor regression in patients. These results demonstrate that mitotic arrest is not responsible for the efficacy of paclitaxel, which occurs because of chromosome missegregation on highly abnormal, multipolar spindles. This mechanistic insight may be used to improve selection of future antimitotic drugs and to identify a biomarker with which to select patients likely to benefit from paclitaxel.

Tumor biology correlates with rates of breast-conserving surgery and pathologic complete response after neoadjuvant chemotherapy for breast cancer: findings from the ACOSOG Z1071 (Alliance) prospective multicenter clinical trial

Objective:To determine the impact of tumor biology on rates of breast-conserving surgery and pathologic complete response (pCR) after neoadjuvant chemotherapy. Background:The impact of tumor biology on the rate of breast-conserving surgery after neoadjuvant chemotherapy has not been well studied. Methods:We used data from ACOSOG Z1071, a prospective, multicenter study assessing sentinel lymph node surgery after neoadjuvant chemotherapy in patients presenting with node-positive breast cancer from 2009 through 2011, to determine rates of breast-conserving surgery and pCR after chemotherapy by approximated biologic subtype. Results:Of the 756 patients enrolled on Z1071, 694 had findings available from pathologic review of breast and axillary specimens from surgery after chemotherapy. Approximated subtype was triple-negative in 170 (24.5%), human epidermal growth factor receptor 2 (HER2)-positive in 207 (29.8%), and hormone-receptor-positive, HER2-negative in 317 (45.7%) patients. Patient age, clinical tumor and nodal stage at presentation did not differ across subtypes. Rates of breast-conserving surgery were significantly higher in patients with triple-negative (46.8%) and HER2-positive tumors (43.0%) than in those with hormone-receptor-positive, HER2-negative tumors (34.5%) (P = 0.019). Rates of pCR in both the breast and axilla were 38.2% in triple-negative, 45.4% in HER2-positive, and 11.4% in hormone-receptor-positive, HER2-negative disease (P < 0.0001). Rates of pCR in the breast only and the axilla only exhibited similar differences across tumor subtypes. Conclusions:Patients with triple-negative and HER2-positive breast cancers have the highest rates of breast-conserving surgery and pCR after neoadjuvant chemotherapy. Patients with these subtypes are most likely to be candidates for less invasive surgical approaches after chemotherapy.

Quantitative Optical Spectroscopy: A Robust Tool for Direct Measurement of Breast Cancer Vascular Oxygenation and Total Hemoglobin Content In vivo

We propose the use of a robust, biopsy needle-based, fiber-optic tool for routine clinical quantification of tumor oxygenation at the time of diagnostic biopsy for breast cancer. The purpose of this study was to show diffuse reflectance spectroscopy as a quantitative tool to measure oxygenation levels in the vascular compartment of breast cancers in vivo via an optical biopsy technique. Thirty-five patients undergoing surgical treatment for breast cancer were recruited for the study at Duke University Medical Center. Diffuse reflectance spectroscopy was performed on the tumors in situ before surgical resection, followed by needle-core biopsy of the optically measured tissue. Hemoglobin saturation and total hemoglobin content were quantified from 76 optical spectra-tissue biopsy pairs, consisting of 20 malignant, 23 benign, and 33 adipose tissues. Hemoglobin saturation in malignant tissues was significantly lower than nonmalignant tissues (P<0.002) and was negatively correlated with tumor size and pathologic tumor category (P<0.05). Hemoglobin saturation was positively correlated with total hemoglobin content in malignant tissues (P<0.02). HER2/neu-amplified tumors exhibited significantly higher total hemoglobin content (P<0.05) and significantly higher hemoglobin saturation (P<0.02), which is consistent with a model of increased angiogenesis and tumor perfusion promoted by HER2/neu amplification. Diffuse reflectance spectroscopy could aid in prognosis and prediction in breast cancer via quantitative assessment of tumor physiology at the time of diagnostic biopsy.

Sentinel node skills verification and surgeon performance: Data from a multicenter clinical trial for early-stage breast cancer

Objective:Marked variations in sentinel lymph node dissection (SLND) technique have been identified, and definitive qualifications for SLND performance remain controversial. Based on previous reports and expert opinion, we predicted that 20 to 30 cases of SLND with axillary lymph node dissection (ALND) would enable surgeons to identify sentinel lymph nodes (SLN). Summary Background Data:In 1999, the American College of Surgeons Oncology Group initiated a prospective trial, Z0010, to evaluate micrometastatic disease in the SLN and bone marrow of women with early-stage breast cancer. Eligible patients included women with biopsy-proven T1/T2 breast cancer and clinically negative lymph nodes who were candidates for lumpectomy and SLND. Methods:Participating surgeons were required to document 20 to 30 SLNDs followed by immediate ALND with failure rates less than 15%. Prior fellowship or residency training in SLND provided exemption from skill requirements. Data for 5237 subjects and 198 surgeons were available for analysis. Results:Surgeons from academic (48.4%), community (28.6%), or teaching-affiliated (19.8%) institutions qualified with 30 SLND + ALND cases (64.6%), 20 cases (22.2%), or exemption (13.1%). Participants used blue dye + radiocolloid in 79.4%, blue dye alone in 14.8%, and radiocolloid alone in 5.7% of cases, achieving a 98.7% SLN identification rate. Patient factors associated with increased SLND failure included increased body mass index and age, whereas tumor location, stage, and histology, presence of nodal metastases, and number of positive nodes were not. Surgeon accrual of fewer than 50 patients was associated with increased SLND failure; however, SLND technique, specific skill qualification, and institution type were not. Conclusions:Using a standard skill requirement, surgeons from a variety of institutions achieved an acceptably low SLND failure rate in the setting of a large multicenter trial, validating the incorporation of SLND into clinical practice.

Repeat Surgery After Breast Conservation for the Treatment of Stage 0 to II Breast Carcinoma A Report From the National Cancer Data Base, 2004-2010

IMPORTANCE Although complete excision of breast cancer is accepted as the best means to reduce local recurrence and thereby improve survival, there is currently no standard margin width for breast conservation surgery. As a result, significant variability exists in the number of additional operations or repeat surgeries patients undergo to establish tumor-negative margins. OBJECTIVE To determine the patient, tumor, and facility factors that influence repeat surgery rates in US patients undergoing breast conservation surgery. DESIGN, SETTING, AND PATIENTS Patients diagnosed as having breast cancer at a Commission on Cancer accredited center from January 1, 2004, through December 31, 2010, and identified via the National Cancer Data Base, a large observational database, were included in the analysis. A total of 316,114 patients with stage 0 to II breast cancer who underwent initial breast conservation surgery were studied. Patients who were neoadjuvantly treated or whose conditions were diagnosed by excisional biopsy were excluded. MAIN OUTCOMES AND MEASURES Patient, tumor, and facility factors associated with repeat surgeries. RESULTS A total of 241,597 patients (76.4%) underwent a single lumpectomy, whereas 74,517 (23.6%) underwent at least 1 additional operation, of whom 46,250 (62.1%) underwent a completion lumpectomy and 28,267 (37.9%) underwent a mastectomy. The proportion of patients undergoing repeat surgery decreased slightly during the study period from 25.4% to 22.7% (P < .001). Independent predictors of repeat surgeries were age, race, insurance status, comorbidities, histologic subtype, estrogen receptor status, pathologic tumor size, node status, tumor grade, facility type and location, and volume of breast cancer cases. Age was inversely associated with repeat surgery, decreasing from 38.5% in patients 18 to 29 years old to 16.5% in those older than 80 years (P < .001). In contrast, larger tumor size was linearly associated with a higher repeat surgery rate (P < .001). Repeat surgeries were most common at facilities located in the Northeast region (26.5%) compared with facilities in the Mountain region, where only 18.4% of patients underwent repeat surgery (P < .001). Academic or research facilities had a 26.0% repeat surgery rate compared with a rate of 22.4% at community facilities (P < .001). CONCLUSIONS AND RELEVANCE Approximately one-fourth of all patients who undergo initial breast conservation surgery for breast cancer will have a subsequent operative intervention. The rate of repeat surgeries varies by patient, tumor, and facility factors and has decreased slightly during the past 6 years.

Identification and Resection of Clipped Node Decreases the False-negative Rate of Sentinel Lymph Node Surgery in Patients Presenting With Node-positive Breast Cancer (T0-T4, N1-N2) Who Receive Neoadjuvant Chemotherapy: Results From ACOSOG Z1071 (Alliance).

Background:The American College of Surgeons Oncology Group Z1071 trial reported a false-negative rate (FNR) of 12.6% with sentinel lymph node (SLN) surgery after neoadjuvant chemotherapy in women presenting with node-positive breast cancer. One proposed method to decrease the FNR is clip placement in the positive node at initial diagnosis with confirmation of clipped node resection at surgery. Methods:Z1071 was a multi-institutional trial wherein women with clinical T0–T4,N1–N2,M0 breast cancer underwent SLN surgery and axillary dissection (ALND) after neoadjuvant chemotherapy. In cases with a clip placed in the node, the clip location at surgery (SLN or ALND) was evaluated. Results:A clip was placed at initial node biopsy in 203 patients. In the 170 (83.7%) patients with cN1 disease and at least 2 SLNs resected, clip location was confirmed in 141 cases. In 107 (75.9%) patients where the clipped node was within the SLN specimen, the FNR was 6.8% (confidence interval [CI]: 1.9%–16.5%). In 34 (24.1%) cases where the clipped node was in the ALND specimen, the FNR was 19.0% (CI: 5.4%–41.9%). In cases without a clip placed (n = 355) and in those where clipped node location was not confirmed at surgery (n = 29), the FNR was 13.4% and 14.3%, respectively. Conclusions:Clip placement at diagnosis of node-positive disease with removal of the clipped node during SLN surgery reduces the FNR of SLN surgery after neoadjuvant chemotherapy. Clip placement in the biopsy-proven node at diagnosis and evaluation of resected specimens for the clipped node should be considered when conducting SLN surgery in this setting.

Axillary Ultrasound After Neoadjuvant Chemotherapy and Its Impact on Sentinel Lymph Node Surgery: Results From the American College of Surgeons Oncology Group Z1071 Trial (Alliance)

PURPOSE The American College of Surgeons Oncology Group Z1071 trial reported a 12.6% false-negative rate (FNR) for sentinel lymph node (SLN) surgery after neoadjuvant chemotherapy (NAC) in cN1 disease. Patients were not selected for surgery based on response, but a secondary end point was to determine whether axillary ultrasound (AUS) after NAC after fine-needle aspiration cytology can identify abnormal nodes and guide patient selection for SLN surgery. PATIENTS AND METHODS Patients with T0-4, N1-2, M0 breast cancer underwent AUS after neoadjuvant chemotherapy. AUS images were centrally reviewed and classified as normal or suspicious lymph nodes. AUS findings were tested for association with pathologic nodal status and SLN FNR. The impact of AUS results to select patients for SLN surgery to reduce the FNR was assessed. RESULTS Postchemotherapy AUS images were reviewed for 611 patients. One hundred thirty (71.8%) of 181 AUS-suspicious patients were node positive at surgery compared with 243 (56.5%) of 430 AUS-normal patients (P < .001). Patients with AUS-suspicious nodes had a greater number of positive nodes and greater metastasis size (P < .001). The SLN FNR was not different based on AUS results; however, using a strategy where only patients with normal AUS undergo SLN surgery would potentially reduce the FNR in Z1071 patients with ≥ two SLNs removed from 12.6% to 9.8% when preoperative AUS results are considered as part of SLN surgery. CONCLUSION AUS is recommended after chemotherapy to guide axillary surgery. An FNR of 9.8% with the combination of AUS and SLN surgery would be acceptable for the adoption of SLN surgery for women with node-positive breast cancer treated with neoadjuvant chemotherapy.

Rapid noninvasive optical imaging of tissue composition in breast tumor margins.

BACKGROUND In women undergoing breast conserving surgery (BCS), up to 60% can require re-excision. Our objective is to develop an optically based technology which can differentiate benign from malignant breast tissues intraoperatively through differences in tissue composition factors. METHODS A prospective study of optical imaging of BCS margins is being performed. Optical images are transformed into tissue composition maps with parameters of total hemoglobin concentration, b-carotene concentration and scattering. The predicted outcome is then compared to the margin-level pathology. RESULTS Fifty-five margins from 48 patients have undergone assessment. Within 34 specimens with pathologically confirmed positive margins, the ratio map of b-carotene/scattering showed the most significant difference reflecting a decrease in adipose and an increase in cell density within malignant margins (p=.002). These differences were notable in both in-situ and invasive disease. CONCLUSIONS We present a novel optical spectral imaging device that provides a rapid, non-destructive assay of the tissue composition of breast tumor margins.

Safety and efficacy of aerobic training in operable breast cancer patients receiving neoadjuvant chemotherapy: A phase II randomized trial

Abstract Background. To evaluate the safety and efficacy of moderate-to-high intensity aerobic training in breast cancer patients receiving neoadjuvant chemotherapy. Methods. Twenty patients with stage IIB–IIIC operable breast cancer were randomly assigned to receive doxorubicin plus cyclophosphamide (AC) or AC in combination with aerobic training (AC + AET) (n = 10/group) for 12 weeks. The AC+ AET group performed three supervised aerobic cycle ergometry sessions per week at 60%–100% of exercise capacity (VO2peak). Safety outcomes included exercise testing as well as treatment- and exercise training-related adverse events (AEs), whereas efficacy outcomes included cardiopulmonary function and patient-reported outcomes (PROs) as measured by a cardiopulmonary exercise test (CPET) and Functional Assessment of Cancer Therapy-Breast (FACT-B) scale. Results. Twelve non-significant ECG abnormalities and three non-life threatening events occurred during CPET procedures. One AE was reported during aerobic training. There were no significant between group differences for clinician-documented events (e.g. pain, nausea) or hematological parameters (ps > 0.05). Attendance and adherence rates to aerobic training were 82% and 66%, respectively. Intention-to-treat analysis indicated that VO2peak increased by 2.6 ± 3.5 ml/kg/min (+ 13.3%) in the AC + AET group and decreased by 1.5 ± 2.2 ml/kg/min (−8.6%) in the AC group (between group difference, p = 0.001). FACT-B increased 11.1 points in the AC + AET group compared to a 1.5 point decrease in the AC group (between group difference, p = 0.685). Conclusion. Moderate-to-high intensity aerobic training when conducted with one-on-one supervision is a safe adjunct therapy associated with improvements in cardiopulmonary function and select PROs during neoadjuvant chemotherapy.