Kimberly J. Van Zee

A Nomogram for Predicting the Likelihood of Additional Nodal Metastases in Breast Cancer Patients With a Positive Sentinel Node Biopsy

AbstractBackground:The standard of care for breast cancer patients with sentinel lymph node (SLN) metastases includes complete axillary lymph node dissection (ALND). However, many question the need for complete ALND in every patient with detectable SLN metastases, particularly those perceived to have a low risk of non-SLN metastases. Accurate estimates of the likelihood of additional disease in the axilla could assist greatly in decision-making regarding further treatment. Methods:Pathological features of the primary tumor and SLN metastases of 702 patients who underwent complete ALND were assessed with multivariable logistic regression to predict the presence of additional disease in the non-SLNs of these patients. A nomogram was created using pathological size, tumor type and nuclear grade, lymphovascular invasion, multifocality, and estrogen-receptor status of the primary tumor; method of detection of SLN metastases; number of positive SLNs; and number of negative SLNs. The model was subsequently applied prospectively to 373 patients. Results:The nomogram for the retrospective population was accurate and discriminating, with an area under the receiver operating characteristic (ROC) curve of 0.76. When applied to the prospective group, the model accurately predicted likelihood of non-SLN disease (ROC, 0.77). Conclusions:We have developed a user-friendly nomogram that uses information commonly available to the surgeon to easily and accurately calculate the likelihood of having additional, non-SLN metastases for an individual patient.

Prevalence of Lymphedema in Women With Breast Cancer 5 Years After Sentinel Lymph Node Biopsy or Axillary Dissection: Objective Measurements

PURPOSE Sentinel lymph node biopsy was adopted for the staging of the axilla with the assumption that it would reduce the risk of lymphedema in women with breast cancer. The aim of this study was to determine the long-term prevalence of lymphedema after SLN biopsy (SLNB) alone and after SLNB followed by axillary lymph node dissection (SLNB/ALND). PATIENTS AND METHODS At median follow-up of 5 years, lymphedema was assessed in 936 women with clinically node-negative breast cancer who underwent SLNB alone or SLNB/ALND. Standardized ipsilateral and contralateral measurements at baseline and follow-up were used to determine change in ipsilateral upper extremity circumference and to control for baseline asymmetry and weight change. Associations between lymphedema and potential risk factors were examined. RESULTS Of the 936 women, 600 women (64%) underwent SLNB alone and 336 women (36%) underwent SLNB/ALND. Patients having SLNB alone were older than those having SLNB/ALND (56 v 52 years; P < .0001). Baseline body mass index (BMI) was similar in both groups. Arm circumference measurements documented lymphedema in 5% of SLNB alone patients, compared with 16% of SLNB/ALND patients (P < .0001). Risk factors associated with measured lymphedema were greater body weight (P < .0001), higher BMI (P < .0001), and infection (P < .0001) or injury (P = .02) in the ipsilateral arm since surgery. CONCLUSION When compared with SLNB/ALND, SLNB alone results in a significantly lower rate of lymphedema 5 years postoperatively. However, even after SLNB alone, there remains a clinically relevant risk of lymphedema. Higher body weight, infection, and injury are significant risk factors for developing lymphedema.

Sentinel lymph node biopsy: is it indicated in patients with high-risk ductal carcinoma-in-situ and ductal carcinoma-in-situ with microinvasion?

Background: Axillary lymph node status is the strongest prognostic indicator of survival for women with breast cancer. The purpose of this study was to determine the incidence of sentinel node metastases in patients with high-risk ductal carcinoma-in-situ (DCIS) and DCIS with microinvasion (DCISM).Methods: From November 1997 to November 1999, all patients who underwent sentinel node biopsy for high-risk DCIS (n = 76) or DCISM (n = 31) were enrolled prospectively in our database. Patients with DCIS were considered high risk and were selected for sentinel lymph node biopsy if there was concern that an invasive component would be identified in the specimen obtained during the definitive surgery. Patients underwent intraoperative mapping that used both blue dye and radionuclide. Excised sentinel nodes were serially sectioned and were examined by hematoxylin and eosin and by immunohistochemistry.Results: Of 76 patients with high-risk DCIS, 9 (12%) had positive sentinel nodes; 7 of 9 patients were positive for micrometastases only. Of 31 patients with DCISM, 3 (10%) had positive sentinel nodes; 2 of 3 were positive for micrometastases only. Six of nine patients with DCIS and three of three with DCISM and positive sentinel nodes had completion axillary dissection; one patient with DCIS had an additional positive node detected by conventional histological analysis.Conclusions: This study documents a high incidence of lymph node micrometastases as detected by sentinel node biopsy in patients with high-risk DCIS and DCISM. Although the biological significance of breast cancer micrometastases remains unclear at this time, these findings suggest that sentinel node biopsy should be considered in patients with high-risk DCIS and DCISM.

Isosulfan blue dye reactions during sentinel lymph node mapping for breast cancer

UNLABELLED In the United States, identification of the sentinel lymph node (SLN) requires the use of (99m)Tc-labeled colloid, 1% isosulfan blue dye, or both to trace the lymphatic drainage of a given neoplasm. We report our experience with adverse reactions to isosulfan blue dye during SLN mapping in breast cancer. A chart review of the breast cancer SLN database was performed; it included 2392 sequential patients who underwent SLN biopsy involving isosulfan blue dye at Memorial Sloan-Kettering Cancer Center from September 12, 1996, to August 17, 2000. Thirty-nine of 2392 patients (1.6%) had a documented allergic reaction during the mapping procedure. Most reactions (69%) produced urticaria, blue hives, a generalized rash, or pruritus. The incidence of hypotensive reactions was 0.5%. Although anaphylaxis after the injection of isosulfan blue dye is rare, this article highlights the need to suspect anaphylaxis when hemodynamic instability occurs after the injection of this compound. Our experience indicates that bronchospasm and respiratory compromise are unusual and that most patients do not require emergent intubation and can be managed with short-term pressor support. In addition, our data indicate that patients with a sulfa allergy do not display a cross-sensitivity to isosulfan blue dye. IMPLICATIONS We report the largest single-institution review of adverse reactions to injection of isosulfan blue dye during sentinel lymph node mapping in breast cancer. Bronchospasm and respiratory compromise are unusual, and most patients can be treated with short-term pressor support. Patients with a sulfa allergy do not display a cross-sensitivity to isosulfan blue dye.

Predicting Nonsentinel Node Status After Positive Sentinel Lymph Biopsy for Breast Cancer: Clinicians Versus Nomogram

BackgroundWith increasing frequency, breast cancer patients and clinicians are questioning the need for completion axillary lymph node dissection (ALND) in the setting of a positive sentinel lymph node (SLN). We previously developed a nomogram to estimate the likelihood of residual disease in the axilla after a positive SLN biopsy result. In this study, we compared the predictions of clinical experts with those generated by the nomogram and evaluated the ability of the nomogram to change clinicians’ behavior.MethodsPathologic features of the primary tumor and SLN metastases of 33 patients who underwent completion ALND were presented to 17 breast cancer specialists. Their predictions for each patient were recorded and compared with results from our nomogram. Subsequently, clinicians were presented with clinical information for eight patients and asked whether they would perform a completion ALND before and after being presented with the nomogram prediction.ResultsThe predictive model achieved an area under the receiver operating characteristic curve of .72 when applied to the test data set of 33 patients. In comparison, the clinicians as a group were associated with an area under the receiver operating characteristic curve of .54 (P < .01 vs. nomogram). With regard to performing a completion ALND, providing nomogram results did not alter surgical planning.ConclusionsOur predictive model seemed to substantially outperform clinical experts. Despite this, clinicians were unlikely to change their surgical plan based on nomogram results. It seems that most clinicians can improve their predictive ability by using the nomogram to predict the likelihood of additional non-SLN metastases in a woman with a positive SLN biopsy result.

Nomogram for Predicting the Risk of Local Recurrence After Breast-Conserving Surgery for Ductal Carcinoma In Situ

PURPOSE While the mortality associated with ductal carcinoma in situ (DCIS) is minimal, the risk of ipsilateral breast tumor recurrence (IBTR) after breast-conserving surgery (BCS) is relatively high. Radiation therapy (RT) and antiestrogen agents reduce the risk of IBTR and are considered standard treatment options after BCS. However, they have never been proven to improve survival, and in themselves carry rare but serious risks. Individualized estimation of IBTR risk would assist in decision making regarding the various treatment options for women with DCIS. PATIENTS AND METHODS From 1991 to 2006, 1,868 consecutive patients treated with BCS for DCIS were identified. A multivariate Cox proportional hazards model was constructed using the 1,681 in whom data were complete. Ten clinical, pathologic, and treatment variables were built into a nomogram estimating probability of IBTR at 5 and 10 years after BCS. The model was validated for discrimination and calibration using bootstrap resampling. RESULTS The DCIS nomogram for prediction of 5- and 10-year IBTR probabilities demonstrated good calibration and discrimination, with a concordance index of 0.704 (bootstrap corrected, 0.688) and a concordance probability estimate of 0.686. Factors with the greatest influence on risk of IBTR in the model included adjuvant RT or endocrine therapy, age, margin status, number of excisions, and treatment time period. CONCLUSION The DCIS nomogram integrates 10 clinicopathologic variables to provide an individualized risk estimate of IBTR in a woman with DCIS treated with BCS. This tool may assist in individual decision making regarding various treatment options and help avoid over- and undertreatment of noninvasive breast cancer.

Oral gossypol in the treatment of patients with refractory metastatic breast cancer: a phase I/II clinical trial

Gossypol has demonstrated in vitro effects on cell cycle regulation and anti-tumor activity against mammary carcinoma cell lines. This Phase I/II study assesses both the effect of gossypol on cell cycle regulatory proteins in vivo and the clinical effect. Twenty women with refractory metastatic breast cancer received oral gossypol at daily doses between 30 and 50mg per day. Gossypol plasma levels were measured (n=8) and the modulation of the retinoblastoma (Rb) gene protein and Cyclin D1 was assessed by serial biopsies (n=4). Grade I–II toxicities with gossypol treatment included nausea in 30% of patients, fatigue 15%, emesis 15%, altered taste sensation 15% and diarrhea in 10% of patients. Two of the three patients receiving 50mg/day experienced dose limiting dermatologic toxicity (grade III). One patient had a minor response and two patients had stable disease with >50 decline in serial assessments of the serum tumor markers. Immunohistochemical analysis of cyclin D1 and Rb expression in serial biopsies of four patients revealed both a concurrent decrease in cyclin D1 expression and an increase in nuclear Rb expression in three patients. The maximal tolerated dose (MTD) of gossypol was 40mg/day. Gossypol appears to affect the expression of Rb protein and cyclin D1 in breast cancer metastases at doses achievable, yet had negligible antitumor activity against anthracycline and taxane refractory metastatic breast cancer. The cell cycle regulatory effects of gossypol suggest a potential role for gossypol as a modulating agent in conjunction with other cell cycle specific compounds.

Predictors of intrusive thoughts and avoidance in women with family histories of breast cancer

Having a family history of cancer is an important predictor of lifetime cancer risk. Individuals with family histories of cancer have been reported to experience symptoms of general distress and to have frequent intrusive thoughts and avoidance regarding cancer. To date, little is known about predictors of such distress. A relation between perception of cancer risk and distress has been suggested, but the possibility that prior cancer-related events may contribute to distress in these women has received little attention. The major aim of the study was to examine the contribution of the past experience of the death of a parent from cancer to distress in women at familiar risk for breast cancer.Women with family histories of breast cancer (Risk Group, N=46) were assessed on the day of their yearly mammography screening and four to eight weeks after normal result notification in order to confirm the generalizability of their distress. Their levels of intrusive thoughts, avoidance, and perceived lifetime risk for breast cancer were significantly higher than those of women with no family histories of cancer who were not undergoing mammography (Comparison Group, N=43), and this was true on both assessment days. Among the women in the Risk Group, those whose parent (s) had died of cancer had the highest levels of intrusive thoughts, avoidance, and perceived risk. Results suggested that perceived risk mediated the effect of this event on intrusive thoughts and avoidance regarding breast cancer. The findings are discussed in terms of theories of cognitive responses to traumatic and stressful life events. Implications for future research and interventions are discussed.

Issues of regret in women with contralateral prophylactic mastectomies.

Background: Patients with a history of carcinoma of one breast have an estimated risk of 0.5% to 0.75% per year of developing a contralateral breast cancer. This risk prompts many women to consider contralateral prophylactic mastectomy (CPM) as a preventive measure. Virtually nothing is known about patient acceptance following CPM. We have developed a National Prophylactic Mastectomy Registry comprised of a volunteer population of 817 women from 43 states who have undergone prophylactic (unilateral or bilateral) mastectomy.Methods: Of the 346 women with CPM who responded to national notices, 296 women returned detailed questionnaires. The information obtained included patient demographics, family history, reproductive history, ipsilateral breast cancer staging and treatment, as well as issues involving the CPM.Results: At median follow-up of 4.9 years, the respondents were primarily married (79%), white (97%) women who had some level of college education or above (81%). These women cited the following reasons for choosing CPM: (1) physician advice regarding the high risk of developing contralateral breast cancer (30%); (2) fear of developing more breast cancer (14%); (3) desire for cosmetic symmetry (10%); (4) family history (7%); (5) fibrocystic breast disease (4%); (6) a combination of all of these reasons (32%); (7) other (2%); and (8) unknown (1%). Eighteen of the 296 women (6%) expressed regrets regarding their decision to undergo CPM. Unlike women with bilateral prophylactic mastectomies, regrets tended to be less common in the women with whom the discussion of CPM had been initiated by their physician (5%) than in the women who had initiated the discussion themselves (8%) (P = ns). Family history and stage of index lesion had no impact on regret status. The reasons for regret included: (1) poor cosmetic result, either of the CPM or of the reconstruction (39%); (2) diminished sense of sexuality (22%); (3) lack of education regarding alternative surveillance methods or CPM efficacy (22%); and (4) other reasons (17%).Conclusions: To minimize the risk of regrets in women contemplating CPM, it is imperative that these women be counseled regarding an estimation of contralateral breast cancer risk, the alternatives to CPM, and the efficacy of CPM. In addition, these women should have realistic expectations of the cosmetic outcomes of surgery and understand the potential impact on their body image.

The accuracy of sentinel lymph node biopsy in multicentric and multifocal invasive breast cancers

BACKGROUND Sentinel lymph node biopsy (SLNB) has proved to be an accurate alternative to complete axillary lymph node dissection (ALND) in clinically node-negative breast cancer patients. Multicentric (MC) and multifocal (MF) invasive breast cancers are considered to be relative contraindications to SLNB. We examine the accuracy of SLNB in patients with MC and MF invasive breast cancers. STUDY DESIGN From September 1996 to August 2001, a total of 3,501 patients with clinically node-negative breast cancer underwent SLNB using both blue dye and radioisotope at our institution. A total of 70 patients had MC or MF invasive breast cancer, a successful SLNB, and mastectomy for local control. All had >/=10 axillary nodes excised (including the SLN) in a planned ALND. Exclusion criteria included MC and MF in situ carcinoma; breast conservation; previous breast irradiation, ALND, or SLNB; recurrent breast cancer; neoadjuvant chemotherapy; or ALND based solely on SLNB pathologic examination. RESULTS; The incidence of axillary metastases was 54% (38 of 70). SLNB accuracy was 96% (67 of 70), sensitivity 92% (35 of 38), and false-negative rate 8% (3 of 38). All patients with an inaccurate SLNB had a dominant invasive tumor >5 cm and one patient had palpable axillary disease intraoperatively. The SLN was the only site of axillary metastasis in 37% (14 of 38). Results were compared with those of published SLNB validation studies, most of which reflect experience with single-site invasive breast cancers. No statistically significant difference was noted for accuracy, sensitivity, or false-negative rate. CONCLUSIONS SLNB accuracy in MC and MF disease is comparable with that of published validation studies. MC and MF patients with a dominant T3 tumor (>5 cm) or axillary disease palpable intraoperatively should have a concurrent formal ALND. Our retrospective data suggest SLNB may be used as a reliable alternative to conventional ALND in selected patients with MC or MF disease. Further studies in this patient population are warranted.