Arpana Naik

The Risk of Axillary Relapse After Sentinel Lymph Node Biopsy for Breast Cancer Is Comparable With That of Axillary Lymph Node Dissection: A Follow-up Study of 4008 Procedures

Objective:We sought to identify the rate of axillary recurrence after sentinel lymph node (SLN) biopsy for breast cancer. Summary Background Data:SLN biopsy is a new standard of care for axillary lymph node staging in breast cancer. Nevertheless, most validated series of SLN biopsy confirm that the SLN is falsely negative in 5–10% of node-positive cases, and few studies report the rate of axillary local recurrence (LR) for that subset of patients staged by SLN biopsy alone. Methods:Through December of 2002, 4008 consecutive SLN biopsy procedures were performed at Memorial Sloan-Kettering Cancer Center for unilateral invasive breast cancer. Patients were categorized in 4 groups: SLN-negative with axillary lymph node dissection (ALND; n = 326), SLN-negative without ALND (n = 2340), SLN-positive with ALND (n = 1132), and SLN-positive without ALND (n = 210). Clinical and pathologic characteristics and follow-up data for each of the 4 cohorts were evaluated with emphasis on patterns of axillary LR. Results:With a median follow-up of 31 months (range, 1–75), axillary LR occurred in 10/4008 (0.25%) patients overall. In 3 cases (0.07%) the axillary LR was the first site of treatment failure, in 4 (0.1%) it was coincident with breast LR, and in 3 (0.07%) it was coincident with distant metastases. Axillary LR was more frequent among the unconventionally treated SLN-positive/no ALND patients than in the other 3 conventionally treated cohorts (1.4% versus 0.18%, P = 0.013). Conclusions:Axillary LR after SLN biopsy, with or without ALND, is a rare event, and this low relapse rate supports wider use of SLN biopsy for breast cancer staging. There is a low-risk subset of SLN-positive patients in whom completion ALND may not be required.

A declining rate of completion axillary dissection in sentinel lymph node-positive breast cancer patients is associated with the use of a multivariate nomogram.

Objective:To compare sentinel lymph node (SLN)-positive breast cancer patients who had completion axillary dissection (ALND) with those who did not, with particular attention to clinicopathologic features, nomogram scores, rates of axillary local recurrence (LR), and changes in treatment pattern over time. Background:While conventional treatment of SLN-positive patients is to perform ALND, there may be a low-risk subgroup of SLN-positive patients in whom ALND is not required. A multivariate nomogram that predicts the likelihood of residual axillary disease may assist in identifying this group. Methods:Among 1960 consecutive SLN-positive patients (1997–2004), 1673 (85%) had ALND (“SLN+/ALND”) and 287 (15%) did not (“SLN+/no ALND”). We compare in detail the clinicopathologic features, nomogram scores, and rates of axillary LR between groups. Results:Compared with the SLN+/ALND group, patients with SLN+/no ALND were older, had more favorable tumors, were more likely to have breast conservation, had a lower median predicted risk of residual axillary node metastases (9% vs. 37%, P < 0.001), and had a marginally higher rate of axillary LR (2% vs. 0.4%, P = 0.004) at 23 to 30 months’ follow-up; half of all axillary LR in SLN+/no ALND patients were coincident with other local or distant sites. For patients in whom intraoperative frozen section was either negative or not done, the rate of completion ALND declined from 79% in 1997 to 62% in 2003 to 2004 but varied widely by surgeon, ranging from 37% to 100%. For 10 of 10 evaluable surgeons, the median nomogram scores in the SLN+/no ALND group were ≤10.5. Conclusions:SLN+/no ALND breast cancer patients, a selected group with relatively favorable disease characteristics, had a 9% predicted likelihood of residual axillary disease by nomogram but an observed axillary LR of 2%. A gradual and significant decline over time in the rate of completion ALND is associated with, but not entirely explained by, the institution of a predictive nomogram. It is reasonable to omit ALND for a low-risk subset of SLN-positive patients.

Screening for Breast Cancer: Systematic Evidence Review Update for the U. S. Preventive Services Task Force

Background This systematic review is an update of evidence since the 2002 U.S. Preventive Services Task Force (USPSTF) recommendation on breast cancer screening.

The Enhanced Tumor Selectivity of an Oncolytic Vaccinia Lacking the Host Range and Antiapoptosis Genes SPI-1 and SPI-2

The ability of cancer cells to evade apoptosis may permit survival of a recombinant vaccinia lacking antiapoptotic genes in cancer cells compared with normal cells. We have explored the deletion of two vaccinia virus host range/antiapoptosis genes, SPI-1 and SPI-2, for their effects on the viral replication and their ability to induce cell death in infected normal and transformed cells in vitro. Indeed, in three paired normal and transformed cell types, the SPI-1 and SPI-2 gene-deleted virus (vSP) preferentially replicates in transformed cells or p53-null cells when compared with their normal counterparts. This selectivity may be derived from the fact that vSP-infected normal cells died faster than infected cancer cells. A fraction of infected cells died with evidence of necrosis as shown by both flow cytometry and detection of high-mobility group B1 protein released from necrotic cells into the culture supernatant. When administered to animals, vSP retains full ability to replicate in tumor tissues, whereas replication in normal tissues is greatly diminished. In a model of viral pathogenesis, mice treated with vSP survived substantially longer when compared with mice treated with the wild-type virus. The mutant virus vSP displayed significant antitumoral effects in an MC38 s.c. tumor model in both nude (P < 0.001) and immunocompetent mice (P < 0.05). We conclude that this recombinant vaccinia vSP shows promise for oncolytic virus therapy. Given its enhanced tumor selectivity, improved safety profile, and substantial oncolytic effects following systemic delivery in murine models, it should also serve as a useful vector for tumor-directed gene therapy.

Intratumor mapping of intracellular water lifetime: metabolic images of breast cancer?

Shutter‐speed pharmacokinetic analysis of dynamic‐contrast‐enhanced (DCE)‐MRI data allows evaluation of equilibrium inter‐compartmental water interchange kinetics. The process measured here – transcytolemmal water exchange – is characterized by the mean intracellular water molecule lifetime (τi). The τi biomarker is a true intensive property not accessible by any formulation of the tracer pharmacokinetic paradigm, which inherently assumes it is effectively zero when applied to DCE‐MRI. We present population‐averaged in vivo human breast whole tumor τi changes induced by therapy, along with those of other pharmacokinetic parameters. In responding patients, the DCE parameters change significantly after only one neoadjuvant chemotherapy cycle: while Ktrans (measuring mostly contrast agent (CA) extravasation) and kep (CA intravasation rate constant) decrease, τi increases. However, high‐resolution, (1 mm)2, parametric maps exhibit significant intratumor heterogeneity, which is lost by averaging. A typical 400 ms τi value means a trans‐membrane water cycling flux of 1013 H2O molecules s−1/cell for a 12 µm diameter cell. Analyses of intratumor variations (and therapy‐induced changes) of τi in combination with concomitant changes of ve (extracellular volume fraction) indicate that the former are dominated by alterations of the equilibrium cell membrane water permeability coefficient, PW, not of cell size. These can be interpreted in light of literature results showing that τi changes are dominated by a PW(active) component that reciprocally reflects the membrane driving P‐type ATPase ion pump turnover. For mammalian cells, this is the Na+,K+‐ATPase pump. These results promise the potential to discriminate metabolic and microenvironmental states of regions within tumors in vivo, and their changes with therapy.

Factors influencing accuracy of axillary sentinel lymph node frozen section for breast cancer

BACKGROUND Intraoperative sentinel lymph node (SLN) frozen section (FS) guides immediate axillary lymph node dissection in breast cancer patients. METHODS The Oregon Health & Science University pathology database was searched for SLN FS From October 1999 to January 1, 2009. Slides of positive cases were reviewed and metastasis sizes measured. RESULTS Of 416 cases, 129 were positive (31%) on permanent sections and immunohistochemistry, with 79 concordant and 50 false-negative FS. Accuracy was 88%, sensitivity 61%, and specificity 100%. FS accuracy for lobular carcinoma (76%) was lower than for invasive ductal carcinoma (88%) (P = .048). FS accuracy significantly differed by size of nodal tumor. For 49 cases of tumor </= 2 mm (isolated tumor cells plus micrometastases), the accuracy of FS was 18%; for 77 cases of >2-mm metastases, accuracy was 90% (P < .0001). CONCLUSIONS False-negative FS were predominantly small nodal tumor deposits not sampled at FS. Although accuracy was lower, SLN FS is still beneficial in lobular carcinoma, but not ductal carcinoma in situ.

Early Prediction and Evaluation of Breast Cancer Response to Neoadjuvant Chemotherapy Using Quantitative DCE-MRI

The purpose is to compare quantitative dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) metrics with imaging tumor size for early prediction of breast cancer response to neoadjuvant chemotherapy (NACT) and evaluation of residual cancer burden (RCB). Twenty-eight patients with 29 primary breast tumors underwent DCE-MRI exams before, after one cycle of, at midpoint of, and after NACT. MRI tumor size in the longest diameter (LD) was measured according to the RECIST (Response Evaluation Criteria In Solid Tumors) guidelines. Pharmacokinetic analyses of DCE-MRI data were performed with the standard Tofts and Shutter-Speed models (TM and SSM). After one NACT cycle the percent changes of DCE-MRI parameters Ktrans (contrast agent plasma/interstitium transfer rate constant), ve (extravascular and extracellular volume fraction), kep (intravasation rate constant), and SSM-unique τi (mean intracellular water lifetime) are good to excellent early predictors of pathologic complete response (pCR) vs. non-pCR, with univariate logistic regression C statistics value in the range of 0.804 to 0.967. ve values after one cycle and at NACT midpoint are also good predictors of response, with C ranging 0.845 to 0.897. However, RECIST LD changes are poor predictors with C = 0.609 and 0.673, respectively. Post-NACT Ktrans, τi, and RECIST LD show statistically significant (P < .05) correlations with RCB. The performances of TM and SSM analyses for early prediction of response and RCB evaluation are comparable. In conclusion, quantitative DCE-MRI parameters are superior to imaging tumor size for early prediction of therapy response. Both TM and SSM analyses are effective for therapy response evaluation. However, the τi parameter derived only with SSM analysis allows the unique opportunity to potentially quantify therapy-induced changes in tumor energetic metabolism.

Impact of American College of Surgeons Oncology Group Z0011 and National Surgical Adjuvant Breast and Bowel Project B-32 trial results on surgeon practice in the Pacific Northwest

BACKGROUND Recent clinical trials have suggested no survival benefit for completion axillary node dissection (CALND) after sentinel lymph node biopsy (American College of Surgeons Oncology Group Z0011) and no clinically meaningful benefit for the routine use of immunohistochemistry (National Surgical Adjuvant Breast and Bowel Project B-32) in clinically node-negative breast cancer. METHODS A 12-question electronic survey was distributed to members of 3 Pacific Northwest surgical societies. Surgeons were queried regarding the impact of the trial results on their surgical management of breast cancer. RESULTS The 181 respondents reported performing fewer CALNDs (63%), fewer intraoperative frozen sections (21%), and no immunohistochemistry (12%) because of trial data. However, 28% of surgeons continued to perform CALND in patients with 1 to 2 positive sentinel lymph nodes undergoing lumpectomy and postoperative radiation. CONCLUSIONS Recent trial data have impacted the performance of CALNDs and the pathological evaluation of sentinel lymph nodes among Pacific Northwest surgeons. Our results suggest a need for regional surgical societies to disseminate practice-changing trial data to members.

Comparative Validation of Online Nomograms for Predicting Nonsentinel Lymph Node Status in Sentinel Lymph Node-Positive Breast Cancer

BACKGROUND Completion axillary lymph node dissection is recommended for patients with metastases to the sentinel lymph node (SLN) in breast cancer although nonsentinel lymph nodes (NSLN) are often negative for tumor. Online nomograms are available to predict risk of NSLN disease. OBJECTIVE To compare the accuracy of the Memorial Sloan-Kettering Cancer Center (MSKCC) nomogram (using 9 variables) with the Stanford nomogram (using 3 variables) in predicting NSLN metastasis. SETTING A single academic center. PATIENTS Prospectively maintained database of patients with breast cancer who underwent SLN biopsy from October 1, 1999, through January 31, 2008. METHODS Risk of NSLN metastasis was calculated using each nomograms online calculator. Results from the axillary lymph node dissection were reviewed for positive NSLNs. Nomograms were evaluated using the area under the receiver operating characteristic curve, false-negative rates, positive predictive value, and calibration plot. MAIN OUTCOME MEASURES Nomogram scores and axillary lymph node dissection results. RESULTS Of 579 patients who underwent SLN biopsy, 179 (30.9%) had a positive SLN. For 123 patients who underwent axillary lymph node dissection, the area under the curve for the MSKCC and Stanford nomograms was 0.72 and 0.70, respectively. False-negative rates for nomogram values of 10% or less were low (4.1% for the MSKCC and 7.8% for the Stanford). The positive predictive value for nomogram probabilities of 80% or greater was higher for MSKCC than for Stanford (90.9% vs 61.8%). The Stanford nomogram performed more accurately in low-risk patients with isolated tumor cells or micrometastatic SLN disease; however, the MSKCC nomogram more accurately predicted NSLN outcomes across the entire study population. CONCLUSION Although the MSKCC and Stanford nomograms performed similarly on the basis of the area under the curve, the MSKCC nomogram was consistently more reliable in predicting actual NSLN outcomes.

Sulforaphane bioavailability and chemopreventive activity in women scheduled for breast biopsy

Epidemiologic studies suggest a protective effect of cruciferous vegetables on breast cancer. Sulforaphane (SFN), an active food component derived from crucifers, has been shown to be effective in breast cancer chemoprevention. This study evaluated the chemopreventive effect of SFN on selective biomarkers from blood and breast tissues. In a 2- to 8-week double-blinded, randomized controlled trial, 54 women with abnormal mammograms and scheduled for breast biopsy were randomized to consume a placebo or a glucoraphanin (GFN) supplement providing SFN (n = 27). Plasma and urinary SFN metabolites, peripheral blood mononuclear cell (PBMC) histone deacetylase (HDAC) activity, and tissue biomarkers (H3K18ac, H3K9ac, HDAC3, HDAC6, Ki-67, p21) were measured before and after the intervention in benign, ductal carcinoma in situ, or invasive ductal carcinoma breast tissues. Within the supplement group, Ki-67 (P = 0.003) and HDAC3 (P = 0.044) levels significantly decreased in benign tissue. Pre-to-postintervention changes in these biomarkers were not significantly different between treatment groups after multiple comparison adjustment. GFN supplementation was associated with a significant decrease in PBMC HDAC activity (P = 0.04). No significant associations were observed between SFN and examined tissue biomarkers when comparing treatment groups. This study provides evidence that GFN supplementation for a few weeks is safe but may not be sufficient for producing changes in breast tissue tumor biomarkers. Future studies employing larger sample sizes should evaluate alternative dosing and duration regimens to inform dietary SFN strategies in breast cancer chemoprevention. Cancer Prev Res; 8(12); 1184–91. ©2015 AACR.