John V. Kiluk

Significance of Sentinel Lymph Node Micrometastases in Human Breast Cancer

BACKGROUND The significance of micrometastatic disease in the sentinel lymph nodes (SLN) of patients with invasive breast cancer has been questioned. The objective of our study was to review the impact of micrometastatic carcinoma detected by SLN biopsy. STUDY DESIGN Between January 1997 and May 2004, 2,408 patients with invasive breast cancer and an SLN with micrometastatic (N0[i+], N1mi) or no metastatic (N0[i-]) disease were identified through our breast database. Slide review was performed and reclassified by the 6(th) edition of the American Joint Committee on Cancer Staging Manual. Of these, 27 were excluded from analysis because of evidence of macrometastatic disease on slide review or enrollment in the American College of Surgeons Oncology Group Z10 study. RESULTS Of 2,381 patients, 2,108 were N0(i-), 151 were N0(i+), and 122 were N1mi. Overall and disease-free survivals of patients with an N1mi SLN were substantially worse than those in patients with an N0(i-) SLN (p < 0.001 and p=0.006, respectively). Additional positive non-SLNs were identified in 15.5% (15 of 97) of N1mi patients and 9.3% (10 of 107) of N0(i+) patients undergoing completion axillary lymph node dissection. Overall survival of the N0(i+) SLN patients not undergoing axillary dissection was substantially less than those undergoing axillary dissection (p=0.02). CONCLUSIONS Detection of micrometastatic carcinoma (N1mi) in the SLNs of invasive breast cancer patients is a major indicator of poorer survival compared with N0(i-) patients. Although survival of patients with an N0(i+) SLN does not statistically differ from that of N0(i-) patients, 9.3% of these patients had additional axillary nodal disease on axillary dissection, and N0(i+) patients had a decreased survival when axillary dissection was omitted.

Pregnancy-Associated Breast Cancer Patients Can Safely Undergo Lymphatic Mapping

Abstract:  As more women put off pregnancy until their 30s and beyond, the possibility of pregnancy‐associated breast cancer (PABC) will rise. Treatment options for patients with PABC need to consider possible harm to the fetus. The goal of this study is to review our institution’s experience with sentinel lymph node (SLN) biopsies in patients with PABC. A prospectively accrued breast Institutional Review Board (IRB) approved data base was searched under separate IRB approval for cases of SLN biopsy in patients with PABC. Ten patients were identified between 1994 and 2006 out of 5,563 patients. A chart review was performed on all 10 patients. Ten patients with PABC and an average gestation age of 15.8 weeks underwent SLN biopsy. All patients successfully mapped. Positive SLN were identified in 5/10 patients (50%) while there was no evidence of metastases in 5/10 patients (50%). 9/10 (90%) of patients went on to deliver healthy children without any reported problems. One patient (10%) decided to terminate her pregnancy in the first trimester following surgery prior to the start of chemotherapy. SLN biopsy can safely be performed in patients with PABC with minimal risk to the fetus. By performing a SLN biopsy, a large proportion of patients with PABC may be spared the risk of a complete axillary lymph node dissection.

The Effect of Oncotype DX Recurrence Score on Treatment Recommendations for Patients with Estrogen Receptor–Positive Early Stage Breast Cancer and Correlation with Estimation of Recurrence Risk by Breast Cancer Specialists

PURPOSE The Oncotype DX assay predicts likelihood of distant recurrence and improves patient selection for adjuvant chemotherapy in estrogen receptor-positive (ER-positive) early stage breast cancer. This study has two primary endpoints: to evaluate the impact of Oncotype DX recurrence scores (RS) on chemotherapy recommendations and to compare the estimated recurrence risk predicted by breast oncology specialists to RS. METHODS One hundred fifty-four patients with ER-positive early stage breast cancer and available RS results were selected. Clinicopathologic data were provided to four surgeons, four medical oncologists, and four pathologists. Participants were asked to estimate recurrence risk category and offer their chemotherapy recommendations initially without and later with knowledge of RS results. The three most important clinicopathologic features guiding their recommendations were requested. RESULTS Ninety-five (61.7%), 45 (29.2%), and 14 (9.1%) tumors were low, intermediate, and high risk by RS, respectively. RS significantly correlated with tumor grade, mitotic activity, lymphovascular invasion, hormone receptor, and HER2/neu status. Estimated recurrence risk by participants agreed with RS in 54.2% ± 2.3% of cases. Without and with knowledge of RS, 82.3% ± 1.3% and 69.0% ± 6.9% of patients may be overtreated, respectively (p = 0.0322). Inclusion of RS data resulted in a 24.9% change in treatment recommendations. There was no significant difference in recommendations between groups of participants. CONCLUSIONS Breast oncology specialists tended to overestimate the risk of tumor recurrence compared with RS. RS provides useful information that improves patient selection for chemotherapy and changes treatment recommendations in approximately 25% of cases.

Use of Reoperative Sentinel Lymph Node Biopsy in Breast Cancer Patients

BACKGROUND Ipsilateral breast recurrence or second primary breast cancer can develop in patients who have undergone breast conservation and sentinel lymph node biopsy (SLNB). This brings into question the necessity of complete axillary lymph node dissection (CALND) versus a second SLNB (remapping). Our objective is to determine the feasibility of a reoperative SLNB. STUDY DESIGN A review of patients receiving a reoperative SLNB between April 1994 and December 2006 was conducted with IRB approval. Fifty-six patients underwent a second SLNB on the ipsilateral side an average of 42.5 months after their first SLNB. RESULTS Sentinel lymph nodes were successfully remapped in 45 of 56 (80.4%) patients. Of 45 patients successfully remapped, 36 (80%) were node negative and were spared CALND. There was only 1 patient (2.2%) in whom a sentinel lymph node was identified outside of the ipsilateral axilla. At 26 months mean followup for the second SLNB, there have been no axillary recurrences and 1 death. CONCLUSIONS Our findings demonstrate that remapping sentinel nodes in patients with ipsilateral recurrence or new primary breast cancer after SLNB achieved success in 80.4% of patients. Overall, 80.0% (36 of 45) of the successfully remapped patients were spared a CALND.

A mitotically active, cellular tumor stroma and/or inflammatory cells associated with tumor cells may contribute to intermediate or high Oncotype DX Recurrence Scores in low-grade invasive breast carcinomas.

Oncotype DX is an RT-PCR-based 21-gene assay validated to provide prognostic and predictive information in the form of a Recurrence Score in patients with estrogen receptor-positive, lymph node-negative breast cancer. Although the Recurrence Score was shown to correlate with several histopathological tumor features, there is a significant proportion of cases showing an apparent discrepancy between Recurrence Score and risk estimates based on the traditional clinicopathological tumor features. In this study, we tested whether a proliferating, cellular stroma and/or admixed inflammatory cells may result in an artificially increased Recurrence Score in low-grade invasive breast cancers. We analyzed the histopathological features in 141 low-grade invasive breast carcinomas, including 41 special type (tubular, cribriform and mucinous) carcinomas, with available Recurrence Score. The tumor stroma was evaluated for increased cellularity and presence of inflammatory cells. Double immunohistochemical stains for pancytokeratin and Ki-67 was performed to assess the cell proliferation in tumor vs stromal/inflammatory cells. The clinicopathological features of tumors with Recurrence Score <18 (low risk) were compared with those with Recurrence Score ≥18 (intermediate/high risk). Carcinomas associated with Recurrence Score ≥18 showed lower progesterone receptor immunoreactivity, increased stromal cellularity and presence of inflammatory cells associated with the tumor. Double immunohistochemical stains showed significantly increased proliferation in stromal/inflammatory cells compared with carcinoma cells in cases associated with Recurrence Score ≥18. A Ki-67-positive stromal/tumor cells ratio of >1 predicted Recurrence Score ≥18 with an area under the curve of 0.8967 on receiver operator curve analysis (P<0.0001). Our results suggest that the presence of increased stromal cellularity and/or associated inflammatory cells in low-grade invasive breast carcinomas may contribute to an apparently increased risk of recurrence according to Oncotype DX Recurrence Score. Careful assessment and correlation with histopathological features in such cases may help in determining the appropriate patient management.

Male Breast Cancer: Management and Follow‐up Recommendations

Abstract:  National Comprehensive Cancer Network (NCCN) guidelines for female breast cancer treatment and surveillance are well established, but similar guidelines on male breast cancers are less recognized. As an NCCN institution, our objective was to examine practice patterns and follow‐up for male breast cancer compared to established guidelines for female patients. After Institutional Review Board approval, a prospective breast database from 1990 to 2009 was queried for male patients. Medical records were examined for clinico‐pathological factors and follow‐up. The 5‐year survival rates with 95% confidence intervals were estimated using Kaplan–Meier method and Greenwood formula. Of the 19,084 patients in the database, 73 (0.4%) were male patients; 62 had complete data. One patient had bilateral synchronous breast cancer. The median age was 68.8 years (range 29–85 years). The mean/median invasive tumor size was 2.2/1.6 cm (range 0.0–10.0 cm). All cases had mastectomy (29 with axillary node dissection, 23 with sentinel lymph node biopsy only, 11 with sentinel node biopsy followed by completion axillary dissection). Lymph node involvement occurred in 25/63 (39.7%). Based on NCCN guidelines, chemotherapy, hormonal therapy, and radiation are indicated in 34 cases, 62 cases, and 14 cases, respectively. Only 20/34 (59%) received chemotherapy, 51/62 (82%) received hormonal therapy, and 10/14 (71%) received post‐mastectomy radiation. Median follow‐up was 26.2 months (range: 1.6–230.9 months). The 5‐year survival estimates for node positive and negative diseases were 68.5% and 87.5%, respectively (p = 0.3). Despite the rarity of male breast cancer, treatment options based on current female breast tumors produce comparable results to female breast cancer. Increased awareness and a national registry for patients could help improve outcomes and tailor treatment recommendations to the male variant.

Sentinel Lymph Node Biopsy in Patients with Previous Ipsilateral Complete Axillary Lymph Node Dissection

BackgroundPrior ipsilateral completion axillary lymph node dissection (CALND) may be considered a contraindication to performing a sentinel lymph node (SLN) mapping in a patient with recurrent breast carcinoma. However, reoperative SLN biopsy following axillary dissection would determine if alternative lymphatic drainage pathways exist. If nodes were found to contain metastatic disease, staging and locoregional control of the disease could be affected.Materials and MethodsAn institutional breast cancer database and electronic health record (IRB No. 102554) prospectively accrued 6225 patients between 1994 and 2007. Under separate IRB approval (IRB No. 102552), this database was queried for patients with a prior history of CALND who received a SLN biopsy. Patients’ demographic, clinical, and treatment variables were recorded.ResultsOf the 6225 patients, 45 (0.7%) were identified as having previously undergone breast-conservation surgery, CALND, and ipsilateral reoperative SLN mapping and biopsy. Of the 45 patients, 13 (29%) had a successful ipsilateral reoperative SLN mapping and biopsy. Nonaxillary drainage was identified in 5 patients with reoperative SLN biopsy.ConclusionReoperative SLN mapping and biopsy is feasible in the setting of local recurrence after previous CALND. This procedure performed for breast cancer recurrence provides important staging information while identifying extra-axillary drainage that could affect both staging and local control.

Acceptance and adherence to chemoprevention among women at increased risk of breast cancer

BACKGROUND Chemoprevention is an option for women who are at increased risk of breast cancer (five year risk ≥1.7%). It is uncertain, however, how often women accept and complete five years of therapy and whether clinical or demographic factors predict completion. METHODS Medical records were abstracted for 219 women whose five year risk of breast cancer was ≥1.7% and who were offered chemoprevention while attending a high risk breast clinic at the Moffitt Cancer Center. We examined the likelihood of accepting chemoprevention and completing five years of therapy, and potential clinical and demographic predictors of these outcomes, using multivariable logistic regression and survival analysis models. RESULTS There were 118/219 women (54.4%) who accepted a recommendation for chemoprevention and began therapy. The likelihood of accepting chemoprevention was associated with lifetime breast cancer risk and was higher for women with specific high risk conditions (lobular carcinoma in situ and atypical ductal hyperplasia). Women with osteoporosis and those that consumed alcohol were also more likely to accept medication. There were 58/118 (49.2%) women who stopped medication at least temporarily after starting therapy. Based on survival curves, an estimated 60% of women who begin chemoprevention will complete five years of therapy. CONCLUSIONS A substantial percentage of women at increased risk of breast cancer will decline chemoprevention and among those that accept therapy, approximately 40% will not be able to complete five years of therapy because of side effects.

Comparison of Oncotype DX and Mammostrat risk estimations and correlations with histologic tumor features in low-grade, estrogen receptor-positive invasive breast carcinomas

Several molecular tests have been developed to estimate risk of distant recurrence and help clinical decision-making regarding adjuvant chemotherapy in patients with early stage breast carcinoma. Both Oncotype DX, a 21-gene expression profile, and Mammostrat, an immunohistochemistry-based assay, are validated to stratify patients into groups with low, intermediate and high risk of distant recurrence. However, they have not been compared head-to-head and little data are available regarding their correlation with clinicopathologic tumor features. In this study, we compared the clinicopathologic tumor features with risk estimations by Oncotype DX and Mammostrat in 106 low-grade estrogen receptor (ER)-positive breast carcinomas. Double immunohistochemical stain for pancytokeratin and Ki-67 was performed to assess cell proliferation in cancer vs stromal/inflammatory cells. Tumors showing intermediate/high risk by Oncotype DX, but not by Mammostrat, showed increased stromal cellularity, presence of inflammatory cells and increased proliferation in stromal/inflammatory cells. Discrepant cases showing intermediate/high risk by Oncotype DX but low risk by Mammostrat were associated with increased stromal cellularity, presence of inflammatory cells and increased proliferation in stromal/inflammatory cells, compared with concordant cases showing low risk by both assays. Our results suggest that low-grade ER-positive breast carcinomas with increased stromal/inflammatory cell proliferation may show an apparent increased risk of distant recurrence as assessed by Oncotype DX, which uses RNA extracted from a mixture of tumor and stromal/inflammatory cells in the assay. Mammostrat, which examines cancer cells only, may provide a better estimation of likely tumor behavior in a subgroup of low-grade breast carcinomas.

Teaching Medical Students How to Break Bad News with Standardized Patients

One of the biggest challenges that a physician will face is conveying difficult news (CDN) to a patient. The ability to provide this information may either strengthen or destroy the patient–physician relationship. Despite the importance of this skill, formal education for medical students has been limited. To improve upon skill building in the medical student experience, fourth year medical students (on their oncology clerkship) spent 3 hours partaking in a CDN session. During this session, each student had a videotaped encounter with a standardized patient, followed by a small group discussion and review of the tape with other students and a clinician. We evaluated the experience with pre- and post-questionnaires assessing overall knowledge, satisfaction, and specific components of the curriculum. The objective of this study was to review our institution’s educational program focused on teaching techniques for CDN.