Thomas G. Frazier

Sentinel-lymph-node resection compared with conventional axillary-lymph-node dissection in clinically node-negative patients with breast cancer: overall survival findings from the NSABP B-32 randomised phase 3 trial.

BACKGROUND Sentinel-lymph-node (SLN) surgery was designed to minimise the side-effects of lymph-node surgery but still offer outcomes equivalent to axillary-lymph-node dissection (ALND). The aims of National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-32 were to establish whether SLN resection in patients with breast cancer achieves the same survival and regional control as ALND, but with fewer side-effects. METHODS NSABP B-32 was a randomised controlled phase 3 trial done at 80 centres in Canada and the USA between May 1, 1999, and Feb 29, 2004. Women with invasive breast cancer were randomly assigned to either SLN resection plus ALND (group 1) or to SLN resection alone with ALND only if the SLNs were positive (group 2). Random assignment was done at the NSABP Biostatistical Center (Pittsburgh, PA, USA) with a biased coin minimisation approach in an allocation ratio of 1:1. Stratification variables were age at entry (≤ 49 years, ≥ 50 years), clinical tumour size (≤ 2·0 cm, 2·1-4·0 cm, ≥ 4·1 cm), and surgical plan (lumpectomy, mastectomy). SLN resection was done with a blue dye and radioactive tracer. Outcome analyses were done in patients who were assessed as having pathologically negative sentinel nodes and for whom follow-up data were available. The primary endpoint was overall survival. Analyses were done on an intention-to-treat basis. All deaths, irrespective of cause, were included. The mean time on study for the SLN-negative patients with follow-up information was 95·6 months (range 70·1-126·7). This study is registered with ClinicalTrials.gov, number NCT00003830. FINDINGS 5611 women were randomly assigned to the treatment groups, 3989 had pathologically negative SLN. 309 deaths were reported in the 3986 SLN-negative patients with follow-up information: 140 of 1975 patients in group 1 and 169 of 2011 in group 2. Log-rank comparison of overall survival in groups 1 and 2 yielded an unadjusted hazard ratio (HR) of 1·20 (95% CI 0·96-1·50; p=0·12). 8-year Kaplan-Meier estimates for overall survival were 91·8% (95% CI 90·4-93·3) in group 1 and 90·3% (88·8-91·8) in group 2. Treatment comparisons for disease-free survival yielded an unadjusted HR of 1·05 (95% CI 0·90-1·22; p=0·54). 8-year Kaplan-Meier estimates for disease-free survival were 82·4% (80·5-84·4) in group 1 and 81·5% (79·6-83·4) in group 2. There were eight regional-node recurrences as first events in group 1 and 14 in group 2 (p=0·22). Patients are continuing follow-up for longer-term assessment of survival and regional control. The most common adverse events were allergic reactions, mostly related to the administration of the blue dye. INTERPRETATION Overall survival, disease-free survival, and regional control were statistically equivalent between groups. When the SLN is negative, SLN surgery alone with no further ALND is an appropriate, safe, and effective therapy for breast cancer patients with clinically negative lymph nodes. FUNDING US Public Health Service, National Cancer Institute, and Department of Health and Human Services.

Technical outcomes of sentinel-lymph-node resection and conventional axillary-lymph-node dissection in patients with clinically node-negative breast cancer: results from the NSABP B-32 randomised phase III trial

BACKGROUND The goals of axillary-lymph-node dissection (ALND) are to maximise survival, provide regional control, and stage the patient. However, this technique has substantial side-effects. The purpose of the B-32 trial is to establish whether sentinel-lymph-node (SLN) resection can achieve the same therapeutic goals as conventional ALND but with decreased side-effects. The aim of this paper is to report the technical success and accuracy of SLN resection plus ALND versus SLN resection alone. METHODS 5611 women with invasive breast cancer were randomly assigned to receive either SLN resection followed by immediate conventional ALND (n=2807; group 1) or SLN resection without ALND if SLNs were negative on intraoperative cytology and histological examination (n=2804; group 2) in the B-32 trial. Patients in group 2 underwent ALND if no SLNs were identified or if one or more SLNs were positive on intraoperative cytology or subsequent histological examination. Primary endpoints, including survival, regional control, and morbidity, will be reported later. Secondary endpoints are accuracy and technical success and are reported here. This trial is registered with the Clinical Trial registry, number NCT00003830. FINDINGS Data for technical success were available for 5536 of 5611 patients; 75 declined protocol treatment, had no SLNs removed, or had no SLN resection done. SLNs were successfully removed in 97.2% of patients (5379 of 5536) in both groups combined. Identification of a preincision hot spot was associated with greater SLN removal (98.9% [5072 of 5128]). Only 1.4% (189 of 13171) of SLN specimens were outside of axillary levels I and II. 65.1% (8571 of 13 171) of SLN specimens were both radioactive and blue; a small percentage was identified by palpation only (3.9% [515 of 13 171]). The overall accuracy of SLN resection in patients in group 1 was 97.1% (2544 of 2619; 95% CI 96.4-97.7), with a false-negative rate of 9.8% (75 of 766; 95% CI 7.8-12.2). Differences in tumour location, type of biopsy, and number of SLNs removed significantly affected the false-negative rate. Allergic reactions related to blue dye occurred in 0.7% (37 of 5588) of patients with data on toxic effects. INTERPRETATION The findings reported here indicate excellent balance in clinical patient characteristics between the two randomised groups and that the success of SLN resection was high. These findings are important because the B-32 trial is the only trial of sufficient size to provide definitive information related to the primary outcome measures of survival and regional control. Removal of more than one SLN and avoidance of excisional biopsy are important variables in reducing the false-negative rate.

Recurrence of breast carcinoma following immediate reconstruction: a 13-year review.

To evaluate the effect of immediate reconstruction on the incidence, location, detection, and treatment of recurrent breast cancer, a review of 306 patients operated on according to a standard protocol during the 10-year period 1979 through 1988 was performed. Reconstruction techniques included submuscular implants (207), tissue expanders (84), and musculocutaneous flaps (15). During a minimum follow-up period of 3 years with a mean of 6.4 years, 60 patients (19.6 percent) developed recurrent disease, at a mean interval to recurrence of 31 months. The first locations of recurrences were local (16), regional (11), and systemic (33). Recurrence rates by stage included stage I, 7 patients (5.2 percent); stage II, 45 patients (32.1 percent); and stage III, 8 patients (40 percent). It was not possible to include comparisons with internal control groups of patients in our institution who were not reconstructed or who had delayed reconstructions, thereby preventing conclusions based on such comparisons. Our recurrence data are similar to literature reports of recurrence rates in patients who were not reconstructed after mastectomy. Detection and treatment of recurrences were not inhibited by the reconstructions. When radiation therapy was used in the treatment of local recurrences, the development of symptomatic capsular contracture was recorded in 58 percent of the patients. (Plast. Reconstr. Surg. 93: 96, 1994.)

Breast Cancer Cells in the Blood: A Pilot Study

Abstract: The goal of this pilot study was to determine in patients with operable breast cancer the incidence of breast cancer cells present in the blood, the clearance rate after surgical resection of the primary tumor, and the incidence of patients with persistent cancer cells in the blood after the primary tumor was removed. Twenty‐one patients with operable breast cancer had 15 ml venous blood obtained twice prior to surgery and after surgery at 2, 4, 8, 12, 24, and 48 hours and also on days 7 and 14. Immunomagnetic selection of malignant cells was performed on each sample. Cells were then fixed on slides and immunocytochemistry performed on the collected cells. Cells that had a rosette of magnetic beads, cytoplasmic staining for keratin, and malignant morphology were counted as breast cancer cells. Eighteen of 19 of patients had cancer cells detected in at least one of the two blood samples preceding surgical removal of the primary tumor. The incidence of cancer cells in the blood of patients rapidly declined during the 48 hours postsurgery. The incidence of cancer cells in the blood remained stable in approximately 30% of patients to 14 days. The majority of breast cancer patients in this pilot study (even with small tumors and negative nodes) had detectable cancer cells in the blood prior to resection of the primary tumor. These findings justify further investigation. Successful application of this methodology may serve as a powerful indicator of which patients need systemic adjuvant therapy, the effectiveness of systemic adjuvant therapy, tumor recurrence, and early detection of breast cancer.

A Randomized Prospective Comparison of Patient-Assessed Satisfaction and Clinical Outcomes with Radioactive Seed Localization versus Wire Localization

Radioactive seed localization (RSL) has emerged as an alternative to wire localization (WL) in patients with nonpalpable breast cancer. Few studies have prospectively evaluated patient satisfaction and outcomes with RSL. We report the results of a randomized trial comparing RSL to WL in our community hospital. We prospectively enrolled 135 patients with nonpalpable breast cancer between 2011 and 2014. Patients were randomized to RSL or WL. Patients rated the pain and the convenience of the localization on a 5‐point Likert scale. Characteristics and outcomes were compared between groups. Of 135 patients enrolled, 10 were excluded (benign pathology, palpable cancer, mastectomy, and previous ipsilateral cancer) resulting in 125 patients. Seventy patients (56%) were randomized to RSL and 55 (44%) to WL. Fewer patients in the RSL group reported moderate to severe pain during the localization procedure compared to the WL group (12% versus 26%, respectively, p = 0.058). The overall convenience of the procedure was rated as very good to excellent in 85% of RSL patients compared to 44% of WL patients (p < 0.0001). There was no difference between the volume of the main specimen (p = 0.67), volume of the first surgery (p = 0.67), or rate of positive margins (p = 0.53) between groups. RSL resulted in less severe pain and higher convenience compared to WL, with comparable excision volume and positive margin rates. High patient satisfaction with RSL provides another incentive for surgeons to strongly consider RSL as an alternative to WL.

Are the American Society for Radiation Oncology Guidelines Accurate Predictors of Recurrence in Early Stage Breast Cancer Patients Treated with Balloon-Based Brachytherapy?

The American Society for Radiation Oncology (ASTRO) consensus statement (CS) provides guidelines for patient selection for accelerated partial breast irradiation (APBI) following breast conserving surgery. The purpose of this study was to evaluate recurrence rates based on ASTRO CS groupings. A single institution review of 238 early stage breast cancer patients treated with balloon-based APBI via balloon based brachytherapy demonstrated a 4-year actuarial ipsilateral breast tumor recurrence (IBTR) rate of 5.1%. There were no significant differences in the 4-year actuarial IBTR rates between the “suitable,” “cautionary,” and “unsuitable” ASTRO categories (0%, 7.2%, and 4.3%, resp., P = 0.28). ER negative tumors had higher rates of IBTR than ER positive tumors. The ASTRO groupings are poor predictors of patient outcomes. Further studies evaluating individual clinicopathologic features are needed to determine the safety of APBI in higher risk patients.

Infrared Imaging Does Not Predict the Presence of Malignancy in Patients with Suspicious Radiologic Breast Abnormalities

The NoTouch BreastScan (NTBS) is a non‐invasive infrared imaging device which measures thermal gradients in breasts using dual infrared cameras and computer analysis. We evaluated NTBS as a predictor of breast cancer in patients undergoing minimally invasive biopsy. In this IRB‐approved prospective trial, 121 female patients underwent NTBS prior to scheduled tissue biopsy. Twenty‐two patients were excluded due to uninterpretable scans (n = 18), diagnosis of a nonprimary breast malignancy (n = 1), or no biopsy performed (n = 3) for a total of 99 patients. Five patients had bilateral breast biopsies and one patient had two ipsilateral biopsies, resulting in 105 biopsies. Patients were prospectively scanned using a high specificity mode, termed NTBS1. All 99 patients were retrospectively re‐evaluated in a high sensitivity mode, NTBS2. Of 105 biopsies performed in 99 women, 33 (31.4%) were malignant and 72 (68.6%) were benign. NTBS1 demonstrated a sensitivity of 45.5% and a specificity of 88.9%. Of 94 normal contralateral breasts, 9.6% had a positive NTBS1. In the retrospective evaluation, NTBS2 demonstrated a sensitivity of 78.8% and a specificity of 48.6%. Half (50%) of the normal contralateral breasts had a positive NTBS2. NTBS does not accurately predict malignancy in women with suspicious imaging abnormalities. The higher sensitivity mode results in an unacceptable number of false positives, precluding its use. Infrared imaging did not improve the sensitivity or specificity of mammography in this clinical setting.

Effect of Preoperative MRI on Mastectomy and Contralateral Prophylactic Mastectomy rates at a Community Hospital by a Single Surgeon

Magnetic resonance imaging (MRI) use in the preoperative evaluation of newly diagnosed breast cancer (BC) patients is rising. We evaluated MRI as a function of surgical year with respect to mastectomy and contralateral prophylactic mastectomy (CPM) rates by a single surgeon. From January 2000 to December 2010, 1,279 patients with 1,296 breast cancers were identified. Our breast MRI was installed in April 2006. Mastectomy and CPM rates were evaluated by surgical year and stratified as “pre‐MRI” or “MRI” depending on whether surgery occurred before or after April 2006. There was a significant increase in the percentage of patients undergoing MRI in the “pre‐MRI” versus “MRI” era (17.2% versus 78.7%, p < 0.001). In contrast, mastectomy rates decreased with 29.9% undergoing mastectomy before 2006 versus 24.5% after 2006 (p = 0.038). Except for 2007, where CPM rates dropped to 7.1%, CPM rates increased from 16.7% in 2000 to 51.9% in 2010 (p = 0.033). The use of MRI, additional MRI findings and additional MRI biopsies were not associated with the decision for CPM. Age <50 was the only factor associated with CPM (RR = 2.12, p = 0.001). In our community hospital, mastectomy rates have decreased despite the increased use of preoperative MRI. MRI alone may not explain the increasing rates of mastectomy reported in other series. CPM rates have dramatically increased over time, seemingly independent of MRI use. Prospective studies are needed to assess the role of surgeon bias, along with other factors, in surgical decision making.

A Retrospective Study of the Impact of 21-Gene Recurrence Score Assay on Treatment Choice in Node Positive Micrometastatic Breast Cancer

To assess clinical utility of the 21-gene assay (Oncotype DX® Recurrence Score®), we determined whether women with HER2(−)/ER+ pN1mi breast cancer with low (<18) Recurrence Scores results are given adjuvant chemotherapy in a lower proportion than those with high scores (≥31). This was a multicenter chart review of ≥18 year old women with pN1mi breast cancer, HER2(−)/ER+ tumors, ductal/lobular/mixed histology, with the assay ordered on or after 1 January 2007. One hundred and eighty one patients had a mean age of 60.7 years; 82.9% had ECOG performance status 0; 33.7% had hypertension, 22.7% had osteoporosis, 18.8% had osteoarthritis, and 8.8% had type-2 diabetes. Mean Recurrence Score was 17.8 (range: 0–50). 48.6% had a mastectomy; 55.8% had a lumpectomy. 19.8% of low-risk group patients were recommended chemotherapy vs. 57.9% in the intermediate-risk group and 100% in the high-risk group (p < 0.001). A total of 80.2% of the low-risk group were recommended endocrine therapy alone, while 77.8% of the high-risk group were recommended both endocrine and chemotherapy (p < 0.001). The Oncotype DX Recurrence Score result provides actionable information that can be incorporated into treatment planning for women with HER2(−)/ER+ pN1mi breast cancer. The Recurrence Score result has clinical utility in treatment planning for HER2(−)/ER+ pN1mi breast cancer patients.

Abstract P5-17-03: The 12-gene DCIS score assay: Impact on radiation treatment (XRT) recommendations and clinical utility

Background: In the management of DCIS clinicians and patients (pts) must choose between the various options for breast conservation treatment based on an assessment of local recurrence (LR) risk. Traditional clinicopathologic (CP) factors such as age, size, grade, margin width or comedo necrosis, provide an average LR risk derived from clinical trials and population studies. The Oncotype DX® 12-gene assay for DCIS gives individual 10-yr LR risk estimates and has now been validated in two studies in a total of 893 pts. We report the 2nd study assessing the impact of the DCIS Score result on XRT recommendations. In addition, surveys assessing pt and physician confidence will provide insight into the overall clinical utility of the DCIS Score result. Baseline characteristics including the pre-assay LR risk and XRT recommendation are described here; final results on change in XRT recommendation from pre- to post-assay and distribution of the score across the CP factors will be presented. Methods: 13 U.S. sites enrolled pts with DCIS from 3/2014-5/2015. Pts with LCIS but no DCIS, invasive BC, or planned mastectomy were excluded. Data were prospectively collected on CP factors, physician estimates of LR risk, DCIS score, and pre/post XRT recommendation. Each pt had a surgeon and radiation oncologist complete study surveys. Pt surveys were also administered pre/post assay for decision conflict and the STAIT anxiety survey. The LR risk estimates and XRT recommendations were analyzed for all physicians as well as by specialty. Descriptive statistics summarized study variables. 95% Clopper-Pearson Exact CIs were calculated for percent change in XRT recommendation. McNemar9s test was used to determine if the proportion of pts had a significant change in XRT recommendation post assay. Paired t-tests were used to compare physician estimates of recurrence risk pre/post assay. Results: Of the 121 pts enrolled, median age was 61y (34-83) and 80.2% were postmenopausal. Median size was 8mm and 40% were Conclusions: The role of new molecular tools such as the DCIS Score assay that provide individual risk estimates for LR on treatment decisions is evolving. The DCIS pts enrolled in the study reveal inclusion of baseline features like higher nuclear grade (26%), comedo necrosis (55%) and margin width of 1-3mm (47%) that have historically been associated with XRT use. This represents a continued broadening of the assay use from the predominantly lower risk DCIS cohort in the 1st validation study (E5194). The impact on XRT decisions is critical to establishing the clinical utility of the assay. The decision impact analysis, differences in use of the assay among surgeons and radiation oncologists and the impact on overall confidence with the treatment decision will be presented. Citation Format: Manders JB, Kuerer HM, Smith BD, McCluskey C, Farrar WB, Frazier TG, Li L, Leonard CE, Carter DL, Chawla S, Medeiros LE, Guenther JM, Castellini LE, Buchholz DJ, Mamounas EP, Wapnir IL, Horst KC, Chagpar A, Evans SB, Riker AI, Vali FS, Solin LJ, Jablon L, Recht A, Sharma R, Lu R, Sing AP, Hwang ES, White J. The 12-gene DCIS score assay: Impact on radiation treatment (XRT) recommendations and clinical utility. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-17-03.