Abigail S. Caudle

Improved Axillary Evaluation Following Neoadjuvant Therapy for Patients With Node-Positive Breast Cancer Using Selective Evaluation of Clipped Nodes: Implementation of Targeted Axillary Dissection

PURPOSE Placing clips in nodes with biopsy-confirmed metastasis before initiating neoadjuvant therapy allows for evaluation of response in breast cancer. Our goal was to determine if pathologic changes in clipped nodes reflect the status of the nodal basin and if targeted axillary dissection (TAD), which includes sentinel lymph node dissection (SLND) and selective localization and removal of clipped nodes, improves the false-negative rate (FNR) compared with SLND alone. METHODS A prospective study of patients with biopsy-confirmed nodal metastases with a clip placed in the sampled node was performed. After neoadjuvant therapy, patients underwent axillary surgery and the pathology of the clipped node was compared with other nodes. Patients undergoing TAD had SLND and selective removal of the clipped node using iodine-125 seed localization. The FNR was determined in patients undergoing complete axillary lymphadenectomy (ALND). RESULTS Of 208 patients enrolled in this study, 191 underwent ALND, with residual disease identified in 120 (63%). The clipped node revealed metastases in 115 patients, resulting in an FNR of 4.2% (95% CI, 1.4 to 9.5) for the clipped node. In patients undergoing SLND and ALND (n = 118), the FNR was 10.1% (95% CI, 4.2 to 19.8), which included seven false-negative events in 69 patients with residual disease. Adding evaluation of the clipped node reduced the FNR to 1.4% (95% CI, 0.03 to 7.3; P = .03). The clipped node was not retrieved as an SLN in 23% (31 of 134) of patients, including six with negative SLNs but metastasis in the clipped node. TAD followed by ALND was performed in 85 patients, with an FNR of 2.0% (1 of 50; 95% CI, 0.05 to 10.7). CONCLUSION Marking nodes with biopsy-confirmed metastatic disease allows for selective removal and improves pathologic evaluation for residual nodal disease after chemotherapy.

Multidisciplinary considerations in the implementation of the findings from the American College of Surgeons Oncology Group (ACOSOG) Z0011 study: a practice-changing trial.

Surgical management of breast cancer has evolved from routine use of radical mastectomy to less disfiguring and extensive procedures, including breast-conserving approaches, for appropriately selected patients. Whereas this transition occurred over several decades, until recently axillary lymph node dissection (ALND) remained standard practice for patients with both node-positive and node-negative breast cancer. The introduction of sentinel lymph node dissection (SLND) was a major departure from ALND allowing for an alternative for nodal staging with less morbidity for the increasing population of patients presenting with clinically node-negative disease.1,2 Although some early studies suggested a survival advantage for patients who undergo ALND compared with no axillary surgery, the likelihood that removing negative nodes could improve outcomes has been questioned. SLND has become the standard of care for patients with clinically node-negative disease. With fewer nodes removed, pathologists can perform a more detailed examination. This allows for improved staging and increases the detection of small-volume metastases. As the population of patients with small burden nodal disease has increased, there has been a growing debate regarding the optimal treatment of node-positive disease. The consensus statement from the American Society of Clinical Oncology and the guidelines from the National Comprehensive Cancer Network recommend a completion ALND (cALND) when metastases are identified on SLND.3,4 These recommendations are supported by data from a meta-analysis of 69 trials, which included 8,059 patients who underwent SLND and cALND, where 53% of the patients with a positive SLN were found to have additional disease in non-SLNs.5 The cALND allows for assessment of the total number of nodes involved, which has prognostic and potentially therapeutic implications. The American Joint Committee on Cancer staging system includes designations for metastases in ≥10 lymph nodes (pN3), 4–9 lymph nodes (pN2), and 1–3 lymph nodes (pN1), as well as micrometastasis (pN1mi; >0.2–2.0 mm) and isolated tumor cells (pN0(i +); ≤0.2 mm).6 The extent of nodal disease may have implications in terms of local-regional control as well as use of systemic therapy and regional and nodal irradiation.7,8 Although cALND has been standard practice when SLNs are involved with metastatic disease, many have questioned the need for cALND in patients with small-volume metastases. The meta-analysis previously discussed showed that 53% of patients had additional nodes with metastatic disease on cALND.5 When considering patients with micrometastatic disease in the SLN(s), the rate of non-SLN involvement is as low as 20%; and for patients with isolated tumor cells the rate decreases to 12%.9,10 These findings have prompted a trend toward omitting cALND in selected patients. In an analysis of the surveillance, epidemiology, and end results (SEER) data from 1998 to 2004, up to 16% of SLN-positive patients did not undergo cALND—a trend seen in older women with low-grade, estrogen receptor (ER)-positive tumors. Considering only patients with micrometastasis in the SLN, the proportion treated with SLND alone increased from 21 to 38%.11 Similarly, a review of the National Cancer Data Base (NCDB) data from 1998 to 2005 revealed that 20.8% of patients with a positive SLN did not undergo cALND. To evaluate a more contemporary cohort, these authors analyzed data from patients diagnosed between 2004 and 2005 and found that the proportion of patients who underwent SLND alone increased in patients with micrometastases, whereas the proportion of patients who underwent SLND alone after macrometastases were identified in the SLN declined slightly during the same time period. At a median follow-up of just more than five years, there were no differences in axillary recurrence rates or survival for patients who underwent SLND alone versus SLND with cALND. This was true for patients with both micrometastases and macrometastases in the SLN.12 These data suggest that many clinicians do not believe that cALND plays an important role in the management of patients with small-volume metastases in the SLN. The American College of Surgeons Oncology Group (ACOSOG) recently reported the results of the Z0011 trial—a prospective, randomized trial designed to evaluate the impact of cALND on local-regional recurrence and survival in patients with early-stage breast cancer and a positive SLN. The purpose of this article is to review the results of the Z0011 trial and to discuss how these data can be implemented in multidisciplinary practice.

Predictors of Tumor Progression During Neoadjuvant Chemotherapy in Breast Cancer

PURPOSE Although most breast cancer patients who receive neoadjuvant chemotherapy (NCT) have a tumor response, a small proportion experience progressive disease (PD). Predictors of response have been reported, but predictors for progression have not been identified. We sought to identify predictors of tumor progression during NCT with the ultimate aim of identifying patients who might benefit from a first-line surgical approach or from novel targeted therapies. PATIENTS AND METHODS Data were obtained from reviewing medical records of patients with stage I to III breast cancer who received NCT (anthracycline and/or taxane based). Statistical analysis was performed to compare patients with any response or stable disease with patients with PD. RESULTS One thousand nine hundred twenty-eight patients received NCT; 1,762 patients (91%) had some response, 107 (6%) had stable disease, and 59 (3%) had PD at some point during NCT. Factors predictive of PD included African American race (P = .002), tumor (T) status (P = .002), and American Joint Committee on Cancer clinical stage (P = .02). Histopathologic features of PD were high tumor grade (P = .005), high Ki-67 score (P = .002), and negative estrogen receptor (ER)/progesterone receptor (PR) status (P < .001/P < .001). Pre-NCT T status, race, and ER status were independent predictors of progression in multivariate analysis. Disease progression was a negative predictor of distant disease-free survival and overall survival in multivariate analysis (P < .001). CONCLUSION Factors predictive of PD include race, advanced tumor stage, high nuclear grade, high Ki-67 score, and ER/PR negativity. Because many of these variables are also associated with response to NCT, novel molecular predictors are needed to identify patients at risk for progression on standard NCT.

Selective surgical localization of axillary lymph nodes containing metastases in patients with breast cancer: a prospective feasibility trial.

IMPORTANCE Nodal ultrasonography with needle biopsy of abnormal lymph nodes helps to define the extent of breast cancer before neoadjuvant chemotherapy. A clip can be placed to designate lymph nodes with documented metastases. Targeted axillary dissection or selective removal of lymph nodes known to contain metastases (clip-containing nodes) as well as sentinel lymph nodes (SLNs) may provide more accurate assessment of the pathologic response after neoadjuvant chemotherapy. OBJECTIVE To determine the feasibility of image-guided localization and resection of lymph nodes containing known metastases. DESIGN, SETTING, AND PARTICIPANTS This prospective feasibility trial performed at MD Anderson Cancer Center, Houston, Texas, included 12 patients with axillary nodal metastases confirmed by results of fine-needle aspiration biopsy who had a clip placed in the lymph node targeted for biopsy from December 1, 2012, through November 30, 2013. INTERVENTIONS Preoperative targeting of the clip-containing lymph node under ultrasonographic guidance consisting of wire localization in 2 patients and placement of radioactive iodine I 125 (125I)-labeled seeds in 10 patients. Surgeons removed the localized lymph node before completion axillary lymph node dissection and used radiography of the specimen to confirm removal of the clip-containing lymph node and seed. MAIN OUTCOMES AND MEASURES Confirmation of the removal of the clip-containing lymph node. RESULTS Image-guided localization and selective removal were successful in all 12 patients. Five patients underwent SLN dissection in addition to removal of the clip-containing lymph node. Placement of 125I seeds did not interfere with lymphoscintigraphy or intraoperative identification of SLNs. In 4 of the 5 patients (80%), the clip-containing lymph node was one of the SLNs. Ten patients completed neoadjuvant chemotherapy before surgery. Of the 9 patients who underwent lymph node dissection, 4 (44%) had residual nodal disease after chemotherapy; all had disease identified in the clip-containing lymph node. CONCLUSIONS AND RELEVANCE Axillary lymph nodes marked with a clip can be localized and selectively removed to accomplish targeted axillary dissection, which is technically possible after chemotherapy and is easily performed with other axillary surgery, such as SLN dissection. The ability to add selective removal of the clip-containing lymph nodes to SLN dissection may identify patients for limited nodal surgery after chemotherapy with increased accuracy for determining residual disease compared with SLN identification alone.

Impact of the american college of surgeons oncology group Z0011 criteria applied to a contemporary patient population.

BACKGROUND The American College of Surgeons Oncology Group (ACOSOG) Z0011 trial concluded that axillary lymph node dissection (ALND) may not be necessary for all patients with sentinel lymph node (SLN) metastasis undergoing breast-conserving therapy (BCT). The aim of this study was to assess applicability of Z0011 results to our patient population and determine what percentage may be affected by these results. STUDY DESIGN Patients with clinical T1-2, N0 breast cancer, treated with surgery first between 1994 and 2009, who had 1 to 2 positive SLNs, were included in this study. Kaplan-Meier survival curves were calculated and log-rank used to compare overall survival (OS) and disease-free survival (DFS) for ALND vs SLN dissection (SLND) alone in 2 patient populations: patients undergoing BCT or total mastectomy (TM) and patients undergoing BCT only. RESULTS Of 861 patients, 188 (21.8%) underwent SLND alone. Of 488 (56.7%) patients who underwent BCT, 125 (25.6%) had SLND alone. Of 412 patients undergoing TM, 67 (16.3%) had SLND alone. Patients undergoing ALND were significantly younger, had larger tumors, macrometastasis, and extranodal extension in both populations. Compared with the Z0011 cohort, our BCT patients had more T1 tumors (76.0% vs 69.3%, p = 0.01) and more grade II to III tumors (87.3% vs 76.2%, p < 0.0001). After adjusting for T-stage, there were no significant differences in DFS and OS between patients undergoing SLND alone or ALND in both populations. CONCLUSIONS Examination of our breast cancer patients with Z0011 trial criteria suggests that almost 75% of SLN-positive patients would be candidates to avoid ALND if they undergo BCT.

IL-24 is expressed during wound repair and inhibits TGFα-induced migration and proliferation of keratinocytes

Please cite this paper as: IL‐24 is expressed during wound repair and inhibits TGFα ‐induced migration and proliferation of keratinocytes. Experimental Dermatology 2010; 19: 714–722.

Metastasectomy for stage IV melanoma: For whom and how much?

Although the conventional paradigm for treating metastatic melanoma relies on systemic therapies, a surgical approach should be strongly considered in selected patients. A surgical approach may not be appropriate for all patients, but it can offer a rapid clearance of disease without the toxicity of systemic therapy. Patient selection is of paramount importance for surgery to be effective. The rationale for surgical intervention in the management of metastatic melanoma, selection factors to be considered, published results, and future directions are discussed in this article.

Impact of Progression During Neoadjuvant Chemotherapy on Surgical Management of Breast Cancer

BackgroundAlthough neoadjuvant chemotherapy (NCT) is standard therapy for locally advanced breast cancer, it remains controversial for early-stage disease due to concerns that disease progression may make breast-conservation therapy (BCT), or even operability, impossible. The goal of this study was to determine the impact of disease progression during NCT on surgical management.MethodsWe reviewed clinicopathological data on patients who received NCT for stage I-III breast cancer from 1994 to 2007. Chemotherapy regimens were anthracycline- and/or taxane-based as determined by the treating medical oncologist.ResultsOf 1,928 patients who received NCT, 1,762 (91%) had a partial or complete response, 107 (6%) had stable disease (SD), and 59 (3%) progressed (PD) while receiving at least one regimen. Of the patients with progressive disease, 40 (68%) patients underwent mastectomy, 12 (20%) underwent BCT, and 7 (12%) did not undergo surgery. In patients who underwent mastectomy, only three (8%) were BCT candidates before progression. Overall, disease progression changed the operative plan in 11 (0.5%) patients: 3 developed distant metastasis, 2 developed clinical lymphadenopathy, 3 required mastectomy instead of BCT, 2 became inoperable, and 1 required flap closure.ConclusionsDisease progression while receiving NCT is infrequent (3%), but early identification may allow for change to other, potentially beneficial, therapeutic interventions. Patients with breast cancer who receive NCT should be evaluated frequently for response to therapy. Overall, progression during NCT changes the surgical management in a small proportion of patients.

Identification of Patients With Documented Pathologic Complete Response in the Breast After Neoadjuvant Chemotherapy for Omission of Axillary Surgery

Importance A pathologic complete response (pCR; no invasive or in situ cancer) occurs in 40% to 50% of patients with HER2-positive (HER2+) and triple-negative (TN) breast cancer. The need for surgery if percutaneous biopsy of the breast after neoadjuvant chemotherapy (NCT) indicates pCR in the breast (hereinafter referred to as breast pCR) has been questioned, and appropriate management of the axilla in such patients is unknown. Objective To identify patients among exceptional responders to NCT with a low risk for axillary metastases when breast pCR is documented who may be eligible for an omission of surgery clinical trial design. Design, Setting, and Participants This prospective cohort study at a single-institution academic national comprehensive cancer center included 527 consecutive patients with HER2+/TN (T1/T2 and N0/N1) cancer treated with NCT followed by standard breast and nodal surgery from January 1, 2010, through December 31, 2014. Main Outcomes and Measures Patients who achieved a breast pCR were compared with patients who did not based on subtype, initial ultrasonographic findings, and documented pathologic nodal status. Incidence of positive findings for nodal disease on final pathologic review was calculated for patients with and without pCR and compared using relative risk ratios with 95% CIs. Results The analysis included 527 patients (median age, 51 [range, 23-84] years). Among 290 patients with initial nodal ultrasonography showing N0 disease, 116 (40.4%) had a breast pCR and 100% had no evidence of axillary lymph node metastases after NCT. Among 237 patients with initial biopsy-proved N1 disease, 69 of 77 (89.6%) with and 68 of 160 (42.5%) without a breast pCR had no evidence of residual nodal disease (P < .01). Patients without a breast pCR had a relative risk for positive nodal metastases of 7.4 (95% CI, 3.7-14.8; P < .001) compared with those with a breast pCR. Conclusions and Relevance Breast pCR is highly correlated with nodal status after NCT, and the risk for missing nodal metastases without axillary surgery in this cohort is extremely low. These data provide the fundamental basis and rationale for management of the axilla in clinical trials of omission of cancer surgery when image-guided biopsy indicates a breast pCR.

Outcomes of Sentinel Lymph Node Dissection Alone vs. Axillary Lymph Node Dissection in Early Stage Invasive Lobular Carcinoma: A Retrospective Study of the Surveillance, Epidemiology and End Results (SEER) Database

Background The American College of Surgeons Oncology Group (ACOSOG) Z0011 trial demonstrated no difference in local-regional recurrence (LRR), disease-specific survival (DSS) or overall survival (OS) for sentinel lymph node dissection (SLND) and completion axillary lymph node dissection (ALND) among patients undergoing breast-conserving therapy for clinical T1–T2, N0 breast cancer with 1 or 2 positive SLNs. However, Only 7% of study participants had invasive lobular carcinoma (ILC). Because ILC has a different pattern of metastases, frequently presenting as small foci requiring immunohistochemistry for detection, the applicability of ACOSOG Z0011 trial data to ILC patients is unclear. Study Design We identified all ILC patients in the Surveillance, Epidemiology, and End Results (SEER) database (1998–2009) who met the ACOSOG Z0011 eligibility criteria. Patients were evaluated on the basis of the extent of axillary surgery (SLND alone or ALND), and the clinical outcomes of these 2 groups were compared. Results 1269 patients (393 SLND and 876 ALND) were identified from the SEER database. At a median follow-up time of 71 months, there were no differences in OS or disease-specific survival between the two groups. Conclusion SLND alone may result in outcomes comparable to those achieved with ALND for patients with early-stage ILC who meet the ACOSOG Z0011 eligibility criteria.