Gene expression profiling to predict the risk of locoregional recurrence in breast cancer: a pooled analysis.

The 70-gene signature (MammaPrint) has been developed to predict the risk of distant metastases in breast cancer and select those patients who may benefit from adjuvant treatment. Given the strong association between locoregional and distant recurrence, we hypothesize that the 70-gene signature will also be able to predict the risk of locoregional recurrence (LRR). 1,053 breast cancer patients primarily treated with breast-conserving treatment or mastectomy at the Netherlands Cancer Institute between 1984 and 2006 were included. Adjuvant treatment consisted of radiotherapy, chemotherapy, and/or endocrine therapy as indicated by guidelines used at the time. All patients were included in various 70-gene signature validation studies. After a median follow-up of 8.96 years with 87 LRRs, patients with a high-risk 70-gene signature (n = 492) had an LRR risk of 12.6% (95% CI 9.7-15.8) at 10 years, compared to 6.1% (95% CI 4.1-8.5) for low-risk patients (n = 561; P < 0.001). Adjusting the 70-gene signature in a competing risk model for the clinicopathological factors such as age, tumour size, grade, hormone receptor status, LVI, axillary lymph node involvement, surgical treatment, endocrine treatment, and chemotherapy resulted in a multivariable HR of 1.73 (95% CI 1.02-2.93; P = 0.042). Adding the signature to the model based on clinicopathological factors improved the discrimination, albeit non-significantly [C-index through 10 years changed from 0.731 (95% CI 0.682-0.782) to 0.741 (95% CI 0.693-0.790)]. Calibration of the prognostic models was excellent. The 70-gene signature is an independent prognostic factor for LRR. A significantly lower local recurrence risk was seen in patients with a low-risk 70-gene signature compared to those with high-risk 70-gene signature.

The use of bioimpedance spectroscopy to monitor therapeutic intervention in patients treated for breast cancer related lymphedema.

We performed a multi-institutional analysis to evaluate the ability of bioimpedance spectroscopy (BIS) to capture the impact of lymphedema treatment compared with observation alone in the management of breast cancer related lymphedema (BCRL). We utilized a retrospective review of 50 patients with breast cancer who were evaluated with BIS at baseline and following loco-regional treatment. An analysis was performed comparing changes in L-Dex scores for those patients undergoing treatment for BCRL (n=13) versus those not undergoing intervention (n=37). A second (subset) analysis was also performed on all patients with elevated L-Dex scores compared to baseline prior to undergoing loco-regional treatment (n=32). When comparing the cohort treated for BCRL to those not treated, L-Dex scores were significantly reduced (-4.3 v. 0.1, p=0.005) in the period following intervention (for treated patients). For the subset of patients with elevated L-Dex scores postoperation, the change in L-Dex score following BCRL treatment was significantly reduced (-5.8 v. 0.1, p=0.001) compared with the group observed that had elevated postsurgical L-Dex scores. In this analysis, BIS was able to detect early onset lymphedema and subsequently significant changes (reductions) in L-Dex scores directly related to intervention for BCRL compared with observation alone.

Six-year analysis of treatment-related toxicities in patients treated with accelerated partial breast irradiation on the American Society of Breast Surgeons MammoSite Breast Brachytherapy registry trial.

BACKGROUND: The American Society of Breast Surgeons (ASBrS) enrolled women in a registry trial to prospectively study patients treated with the MammoSite RTS device. This report presents 6-year data on treatment-related toxicities from the trial. METHODS: A total of 1449 primary early-stage breast cancers were treated with accelerated partial breast irradiation (APBI) using the MammoSite device (34 Gy in 10 fractions) in 1440 women. Of these, 1255 case (87%) had invasive breast cancer (IBC) (median size = 10 mm) and 194 cases (13%) had ductal carcinoma in situ (DCIS) (median size = 8 mm). Median follow-up was 59 months. Fisher exact test was performed to correlate categorical covariates with toxicity. RESULTS: Breast seromas were reported in 28% of cases (35.5% with open cavity and 21.7% with closed cavity placement). Also, 13% of all treated breasts developed symptomatic seromas, and 77% of these seromas developed during the 1st year after treatment. There were 172 cases (11.9%) that required drainage to correct. Use of chemotherapy and balloon fill >50 cc were associated with the development of symptomatic seromas. Also, 2.3% of patients developed fat necrosis (FN). The incidence of FN during years 1 and 2 were 0.9% and 0.8%, respectively. Seroma formation, use of hormonal therapy, breast infection, and A/B cup size were associated with fat necrosis. There were 138 infections (9.5%) recorded; 98% occurred during the 1st year after treatment. Chemotherapy and seroma formation were associated with the development of infections. CONCLUSIONS: Treatment-related toxicities 6 years after treatment with APBI using the MammoSite device are similar to those reported with other forms of APBI with similar follow-up.

Local control, toxicity, and cosmesis in women younger than 50 enrolled onto the American Society of Breast Surgeons MammoSite Radiation Therapy System registry trial.

BACKGROUND: The American Society of Breast Surgeons enrolled women onto a registry trial to prospectively study patients treated with the MammoSite Radiation Therapy System (RTS) breast brachytherapy device. This report examines local recurrence (LR), toxicity, and cosmesis as a function of age in women enrolled onto the trial. METHODS: A total of 1449 primary early-stage breast cancers were treated in 1440 women. Of these, 130 occurred in women younger than 50 years of age. Fisher's exact test was performed to correlate age (<50 vs. > or = 50 years) with toxicity and with cosmesis. The association of age with LR failure times was investigated by fitting a parametric model. RESULTS: Women younger than 50 were more likely to develop fat necrosis: 4.6% (6 of 130) vs. 1.8% (24 of 1319) (P = .0456). Other toxicities were comparable. At 2 years, cosmesis was excellent or good in 87% of assessable women aged <50 years (n = 74) and in 94% of assessable older women (n = 751) (P = .0197). At 3 years, this difference disappeared: excellent or good in 90% (56 of 62) of younger women vs. 93% (573 of 614) of older women (P = .2902). The crude LR rate for the group was 1.7% (25 of 1449). There was no statistically significant difference in LR as a function of age. In women <50, 3.1% (4 of 130) developed a LR; in the older patients, 1.6% (21 of 1319) developed LR (3-year actuarial LR rates, 2.9% vs. 1.7%, respectively; P = .2284). CONCLUSIONS: Accelerated partial breast irradiation with the MammoSite RTS results in low toxicity and produces similar cosmesis and local control at 3 years in women younger than 50 when compared with older women.

Improved lymphatic mapping technique for breast cancer.

Breast sentinel lymph node biopsy is becoming more common. However, the best injection technique is not well established. Currently the gold standard is peritumoral injection. However, for upper outer quadrant tumors there is considerable axillary "shine through" which makes the identification of the radioactive sentinel lymph node difficult. We undertook a study to compare an injection in Sappey's subareolar plexus to the gold standard of peritumoral injection. Between December 1997 and March 1998, 85 patients with breast cancer were enrolled in the study. All patients were injected with 2 cc of normal saline containing 1.0 mCi of unfiltered technetium sulfur colloid in Sappey's subareolar plexus in the clock position of the breast cancer. In the operating room the patients underwent a peritumoral injection of 5 cc of 1% isosulfan blue. All blue and radioactive lymph nodes were identified and removed. The majority of the tumors were in the upper outer quadrant and were diagnosed by core biopsy. Only half of the patients had palpable tumors and approximately 25% had previous upper outer quadrant biopsy incisions. Peritumoral blue dye injection yielded an identification rate of 94%, with 99% of these being blue and radioactive. Three patients had radioactive lymph nodes with no blue lymph nodes identified. One of these patients had a micrometastasis. Injection in Sappey's subareolar plexus in the clock position of the tumor drained to the same sentinel lymph node as peritumoral injection. This injection technique solved the two major problems confronting the wide adoption of sentinel lymph node biopsy for breast cancer staging. First, it eliminates axillary "shine through" which will allow nonspecialist surgeons to more easily identify the radioactive axillary sentinel lymph node. Second, it allows for easier isotope injection by the technician or nuclear medicine physician, by eliminating the need for three-dimensional localization. This new technique should allow the majority of breast cancer patients who are treated by nonspecialist surgeons to be offered this less morbid, more accurate procedure.

Detection of carcinoma cells in the blood of breast cancer patients.

BACKGROUND: Breast cancers shed cancer cells into the blood soon after they become invasive. We developed an assay for removing these circulating cancer cells. In this study, we wanted to determine the percentage of early stage and metastatic patients with circulating breast cancer cells. METHODS: Twenty milliliters of blood were drawn from patients with breast cancer. Epithelial cells were removed by immunomagnetic selection and analyzed by flow cytometry, cytomorphology, and immunocystochemistry. RESULTS: Early stage patients averaged 16 epithelial cells per 20 cc blood whereas metastatic patients averaged 122 tumor cells. Cytomorphology and immunostains confirmed that these were cancer cells. Control blood samples had 1.7 squamous epithelial cells per 20 cc blood. CONCLUSION: This assay can identify and characterize circulating breast cancer cells. Metastatic patients had more circulating cells than early stage patients. This assay could screen high-risk patients, determine the need for and monitor response to adjuvant therapy, and detect early recurrence of breast cancer.

Breast Cancer Cells in the Blood: A Pilot Study.

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.

The sentinel node in breast cancer--a multicenter validation study.

BACKGROUND: Pilot studies indicate that probe-guided resection of radioactive sentinel nodes (the first nodes that receive drainage from tumors) can identify regional metastases in patients with breast cancer. To confirm this finding, we conducted a multicenter study of the method as used by 11 surgeons in a variety of practice settings. METHODS: We enrolled 443 patients with breast cancer. The technique involved the injection of 4 ml of technetium-99m sulfur colloid (1 mCi [37 MBq]) into the breast around the tumor or biopsy cavity. "Hot spots" representing underlying sentinel nodes were identified with a gamma probe. Sentinel nodes subjacent to hot spots were removed. All patients underwent a complete axillary lymphadenectomy. RESULTS: The overall rate of identification of hot spots was 93 percent (in 413 of 443 patients). The pathological status of the sentinel nodes was compared with that of the remaining axillary nodes. The accuracy of the sentinel nodes with respect to the positive or negative status of the axillary nodes was 97 percent (392 of 405); the specificity of the method was 100 percent, the positive predictive value was 100 percent, the negative predictive value was 96 percent (291 of 304), and the sensitivity was 89 percent (101 of 114). The sentinel nodes were outside the axilla in 8 percent of cases and outside of level 1 nodes in 11 percent of cases. Three percent of positive sentinel nodes were in nonaxillary locations. CONCLUSIONS: Biopsy of sentinel nodes can predict the presence or absence of axillary-node metastases in patients with breast cancer. However, the procedure can be technically challenging, and the success rate varies according to the surgeon and the characteristics of the patient.

Sentinel lymph node biopsy, an alternative to elective axillary dissection for breast cancer.

BACKGROUND: Axillary metastases remain an important prognostic indicator in breast cancer. Axillary lymphadenectomy (ALND) carries significant morbidity and is unnecessary in most patients with early breast cancer; thus, sentinel lymph node (SLN) biopsy has been advocated for axillary staging. We studied the SLN identification rate and its accuracy in predicting axillary metastases. METHODS: One hundred nineteen women with breast carcinoma underwent SLN and ALND. Lymphoscintigraphy was performed using Technetium99 sulfur colloid supplemented by Isosulfan blue dye. Hematoxylin/eosin-stained lymph node sections were examined by light microscopy. RESULTS: The SLN identification rate was 81%. One SLN was negative (1%) in a patient with axillary disease. SLN histology correctly predicted the absence of axillary disease in 98.6%. Sensitivity, specificity, and positive and negative predictive values were 96%, 100%, 100%, and 99%, respectively. CONCLUSIONS: Sentinel lymph node biopsy accurately predicts total axillary status and is valuable in the surgical staging of breast cancer.

Incidence and predictors of axillary metastasis in T1 carcinoma of the breast.

BACKGROUND: The relatively low incidence (6 to 31 percent) of axillary metastasis in patients with T1 carcinoma of the breast (20 mm or smaller) has led some surgeons to question routine axillary lymphadenectomy (ALND) for patients with no palpable axillary metastases and T1 tumors. This study was undertaken to determine the incidence and predictors of axillary lymph node metastasis in patients with T1 carcinoma of the breast and evaluate the role of sentinel lymphadenectomy (SLND) in this context. STUDY DESIGN: All patients with T1 invasive carcinoma of the breast treated at the John Wayne Cancer Institute between January 1988 and June 1994 were prospectively studied. The study population was comprised of 259 women who had ALND. Of these patients, 114 were part of a pilot study examining the efficacy of SLND. RESULTS: Of the 259 women, 69 (27 percent) had axillary metastasis. Hematoxylin and eosin staining identified nodal involvement in 13 percent of patients with T1a and T1b tumors (10 mm or less) and in 30 percent of patients with T1c tumors (p = 0.002). Other factors such as age, hormone receptor status, presence of ductal carcinoma in situ, histology, ploidy, and S-phase were not significant predictors of involvement. A sentinel node was identified in 73 patients: this node accurately predicted axillary status in 72 patients, was the only positive node in nine of 16 patients with axillary involvement, and was 100 percent predictive of axillary status when the primary tumor was 10 mm or less. Retrospective immunohistochemical staining revealed an additional seven patients with positive sentinel nodes. With this technique, even T1a lesions had a 15 percent incidence of axillary metastasis. CONCLUSIONS: Tumor size is the only accurate predictor of axillary metastasis in patients with T1 carcinoma of the breast. The significant incidence of axillary involvement from T1 tumors mandates accurate staging, even when the tumor is 10 mm or less in size. Examination of a sentinel lymph node may accurately predict axillary metastasis.

Natural immunity in breast cancer patients during neoadjuvant chemotherapy and after surgery.

Breast cancer is the most common cancer in women. Surgery, and more recently neoadjuvant chemotherapy, are being utilized as the initial treatment for breast cancer; however little is known about their effects on the natural immune system. The natural immune system (natural killer [NK] cells) is thought to be important in immune surveillance, including protection from metastasis during the intravascular tumour seeding that occurs during surgery. To investigate the effects of surgery on the natural immune system, we studied the pre-operative and post-operative peripheral blood lymphocytes (PBL) of 10 patients with stage I or II breast cancer: there was a 71.6 +/- 25.3% post-operative reduction in NK cell function (P < 0.005, Student's paired t-test). To investigate the effects of neoadjuvant chemotherapy and surgery, we examined PBL from five patients with stage III breast cancer: NK cell function dropped 95.7 +/- 1.9% after neoadjuvant chemotherapy, and there was a further 51.0 +/- 23.4% decrease after surgery (P < 0.05, Student's paired t-test). Neither group of patients had decreased numbers of NK cells, changes in the percentage of T helper or suppressor cells, or alterations in the production of cytotoxic factor by NK cells. These findings suggest that the impairment in NK cell function reflects a defect in the ability of NK cells to recognize and/or bind to tumour target cells. We conclude that the initial treatment of breast cancer patients, whether it involves surgery alone or with neoadjuvant chemotherapy, profoundly impairs their natural immune system and could increase the risk of metastasis. Further studies are needed to delineate the mechanism of this derangement in natural immunity and possibly alter its course.

Physical examination and arteriography in patients with penetrating zone II neck wounds.

OBJECTIVE: To review the management of patients with penetrating zone II neck wounds to discern the value of physical examination and proximity arteriography for predicting arterial injury. DESIGN: A retrospective chart review of 178 patients treated for penetrating wounds to the neck. SETTING: A level I trauma facility in Dallas, Tex. PATIENTS: All patients seen from 1987 to 1991 with platysma penetration in zone II of the neck. INTERVENTION: Physical examination, arteriography, and surgical exploration were used to identify patients with arterial injuries in the neck after penetrating trauma. MAIN OUTCOME MEASURES: To identify the presence or absence of an arterial injury. RESULTS: Negative findings on physical examination ruled out an arterial injury in 99% of all patients. Patients with any sign of arterial injury had a 26% incidence of arterial injury confirmed at operation. Of 71 arteriograms in patients without signs or symptoms of arterial injury, only one had an arterial injury requiring operative intervention. CONCLUSIONS: Findings on physical examination are good predictors of arterial injury in patients with penetrating neck wounds and can exclude injury in over 99% of patients. Arteriography is a sensitive test but has a very low yield (1.4%). These findings question whether the current practice of mandatory neck exploration or proximity arteriography is necessary for patients without signs or symptoms of injury who have penetrating wounds of the neck.

Operative morbidity and risk factor assessment in melanoma patients undergoing inguinal lymph node dissection.

A series of 168 patients who underwent 177 inguinal lymph node dissections from 1979 to 1989 were retrospectively reviewed to determine the incidence and severity of postoperative complications as well as the perioperative risk factors associated with them. Operative mortality was 0%, whereas the incidence of moderate to severe wound infection was 11%, skin flap problems 0%, seromas 6%, and hemorrhage 3%. The occurrence of a wound complication increased the average hospital stay from 11 to 12 days. Multivariate risk factor analysis revealed age older than 50, male sex, and smoking to be significant risk factors for developing a wound infection. The use of prophylactic antibiotics and the duration of closed suction catheter drainage were not predictive of wound complications. Overall, 44% of patients experienced some postoperative edema, with only 7% of patients having 1+ edema that lasted longer than 6 months. Combined ilioinguinal lymph node dissection increased the chance of developing moderate to severe edema. These risk factors identify patients at high risk for morbidity, which should lead to improved perioperative care.