Early reflector localization improves the accuracy of localization and excision of a previously positive axillary lymph node following neoadjuvant chemotherapy in patients with breast cancer.

PURPOSE: Clipped axillary lymph node (CALN) localization after neoadjuvant chemotherapy (NAC) for axillary node positive breast cancer can be difficult due to significant shrinkage or disappearance of the CALN after NAC. This study compares wire localization to a radar-based localization system utilizing a reflector that can be placed before or during NAC, in the months before definitive surgery, to facilitate accurate localization and excision of the CALN. METHODS: Between 2016 and 2019, women with T0-4 N1-3 M0 breast cancer who underwent NAC followed by axillary surgery with planned excision of a biopsy positive or clinically suspicious axillary node via wire or reflector localization were identified. A retrospective chart review was performed comparing successful localization and CALN retrieval by each localization technique. RESULTS: Ninety-nine patients met inclusion criteria. Forty-two patients underwent wire localization while 57 patients underwent reflector localization of the CALN. Successful identification of the CALN by wire or reflector was equivalent (83.3% vs 84.2%, respectively). Twenty-two reflectors placed before or during early/mid NAC (early placement) had 100% successful CALN localization and retrieval in the OR. Placement of wire or reflector localization devices within 8 weeks of surgery (late placement) only resulted in 79.2% localization success (p = .02). CONCLUSION: This study suggests a benefit of axillary lymph node reflector placement in the early NAC setting. Early reflector placement allows for more accurate excision of the CALN during axillary surgery after NAC as compared to placement of localization wires or reflectors in the few weeks prior to surgery.

Antiphospholipid antibodies promote tissue factor-dependent angiogenic switch and tumor progression.

Progression to an angiogenic state is a critical event in tumor development, yet few patient characteristics have been identified that can be mechanistically linked to this transition. Antiphospholipid autoantibodies (aPLs) are prevalent in many human cancers and can elicit proangiogenic expression in several cell types, but their role in tumor biology is unknown. Herein, we observed that the elevation of circulating aPLs among breast cancer patients is specifically associated with invasive-stage tumors. By using multiple in vivo models of breast cancer, we demonstrated that aPL-positive IgG from patients with autoimmune disease rapidly accelerates tumor angiogenesis and consequent tumor progression, particularly in slow-growing avascular tumors. The action of aPLs was local to the tumor site and elicited leukocytic infiltration and tumor invasion. Tumor cells treated with aPL-positive IgG expressed multiple proangiogenic genes, including vascular endothelial growth factor, tissue factor (TF), and colony-stimulating factor 1. Knockdown and neutralization studies demonstrated that the effects of aPLs on tumor angiogenesis and growth were dependent on tumor cell-derived TF. Tumor-derived TF was essential for the development of pericyte coverage of tumor microvessels and aPL-induced tumor cell expression of chemokine ligand 2, a mediator of pericyte recruitment. These findings identify antiphospholipid autoantibodies as a potential patient-specific host factor promoting the transition of indolent tumors to an angiogenic malignant state through a TF-mediated pathogenic mechanism.

A phase I-II study of the histone deacetylase inhibitor vorinostat plus sequential weekly paclitaxel and doxorubicin-cyclophosphamide in locally advanced breast cancer.

Histone deacetylases (HDACs) are a family of enzymes that regulate chromatin remodeling and gene transcription. Vorinostat is a panHDAC inhibitor that sensitizes breast cancer cells to taxanes and trastuzumab by suppressing HDAC6 and Hsp90 client proteins. Fifty-five patients with clinical stage IIA-IIIC breast cancer received 12 weekly doses of paclitaxel (80 mg/m(2)) plus vorinostat (200-300 mg PO BID) on days 1-3 of each paclitaxel dose plus trastuzumab (for Her2/neu positive disease only), followed by doxorubicin/cyclophosphamide (60/600 mg/m(2) every 2 weeks plus pegfilgrastim). The primary study endpoint was pathologic complete response (pCR). pCR occurred in 13 of 24 evaluable patients with Her2-positive disease (54, 95 % confidence intervals [CI] 35-72 %), which met the prespecified study endpoint. pCR occurred in 4 of 15 patients with triple negative disease (27, 95 % CI 11-52 %) and none of 12 patients with ER-positive, Her2/neu negative disease (0, 95 % CI 0-24 %), which did not meet the prespecified endpoint. ER-positive tumors exhibited lower Ki67 and higher Hsp70 expression, and HDAC6, Hsp70, p21, and p27 expression were not predictive of response. Vorinostat increased acetylation of Hsp90 and alpha tubulin, and reduced expression of Hsp90 client proteins and HDAC6 in the primary tumor. Combination of vorinostat with weekly paclitaxel plus trastuzumab followed by doxorubicin-cyclophosphamide is associated with a high pCR rate in locally advanced Her2/neu positive breast cancer. Consistent with cell line and xenograft data, vorinostat increased acetylation of Hsp90 and alpha tubulin, and decreased Hsp90 client protein and HDAC6 expression in human breast cancers in vivo.

Cumulative imaging radiation exposure following breast-conservation therapy.

INTRODUCTION: Radiation from medical imaging may induce cellular damage and increase the risk of cancer. While health care workers are restricted to an annual dose of 50 milliSieverts (mSv), the exposure to patients is not typically recorded. After breast-conservation therapy (BCT), patients are subjected to screening mammography, diagnostic breast imaging, and systemic surveillance imaging (SSI). Our objectives are to determine the cumulative radiation exposure of breast cancer survivors after completion of BCT, and to compare exposure levels in two historical cohorts. We also evaluated the indications of SSI. METHODS: We performed a retrospective study of 68 patients with stage I or II breast cancer who received BCT in 1997 or 2002. Cumulative radiation exposure during follow-up from all imaging attributable to the breast cancer diagnosis was recorded, including both breast and non-breast imaging. The indications for SSI were recorded. RESULTS: In the first 5 years after BCT, patients received a median annual dose of 0.92 mSv with no difference between the 1997 and 2002 cohorts. A median of 90% of radiation exposure was due to mammography. From 1997 to 2002, the percentage of patients receiving computed tomography (CT) scans increased. Additional SSI occurred in 65% of patients, with the majority of tests ordered in the asymptomatic patient. Patients with nodal positivity were more likely to receive SSI (p = 0.03). CONCLUSIONS: In the first 5 years after BCT, annual radiation exposure due to imaging was low. However, it seems prudent to consider the risks of radiation exposure when ordering potentially low-yield screening studies in asymptomatic patients.

Systematic review: surveillance for breast cancer in women treated with chest radiation for childhood, adolescent, or young adult cancer.

BACKGROUND: Women treated with therapeutic chest radiation may develop breast cancer. PURPOSE: To summarize breast cancer risk and breast cancer surveillance in women after chest radiation for pediatric or young adult cancer. DATA SOURCES: Studies from MEDLINE, EMBASE, the Cochrane Library, and CINAHL (1966 to December 2008). STUDY SELECTION: Articles were selected to answer any of 3 questions: What is the incidence and excess risk for breast cancer in women after chest radiation for pediatric or young adult cancer? For these women, are the clinical characteristics of breast cancer and the outcomes after therapy different from those of women with sporadic breast cancer in the general population? What are the potential benefits and harms associated with breast cancer surveillance among women exposed to chest radiation? DATA EXTRACTION: Three investigators independently extracted data and assessed study quality. DATA SYNTHESIS: Standardized incidence ratios ranged from 13.3 to 55.5; cumulative incidence of breast cancer by age 40 to 45 years ranged from 13% to 20%. Risk for breast cancer increased linearly with chest radiation dose. Available limited evidence suggests that the characteristics of breast cancer in these women and the outcomes after diagnosis are similar to those of women in the general population; mammography can detect breast cancer, although sensitivity is limited. LIMITATION: The quality of evidence for key questions 2 and 3 is limited by substantial study heterogeneity, variation in study design, and small sample size. CONCLUSION: Women treated with chest radiation have a substantially elevated risk for breast cancer at a young age, which does not seem to plateau. In this high-risk population, there seems to be a benefit associated with early detection. Further research is required to better define the harms and benefits of lifelong surveillance.

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.

Reoperative sentinel lymph node biopsy: a new option for patients with primary or locally recurrent breast carcinoma.

BACKGROUND: Sentinel lymph node (SLN) biopsy is a new standard of care for axillary node staging in patients with primary operable breast cancer. An increasing proportion of these patients undergo breast-conserving surgery, and 10% to 15% will develop local relapse requiring reoperation. Although previous breast or axillary surgery is often considered a contraindication to SLN biopsy, few data support this position. We report our experience with SLN biopsy in the reoperative setting. STUDY DESIGN: We examined the 3,490 consecutive SLN biopsy procedures for breast cancer performed at our institution between September 1996 and July 2001; 32 (1%) of these followed previous axillary surgery: 22 (69%) for breast recurrence after SLN biopsy or axillary lymph node dissection (ALND); 7 (22%) after a recent, failed SLN biopsy or inadequate ALND; and 3 (9%) after earlier axillary surgery for an unrelated condition. RESULTS: SLNs were identified in 24 of 32 (75%) cases and were positive in 3 of 24 (13%). Reoperative SLN biopsy was more successful when less than 10 versus 10 or more nodes had been removed previously (87% versus 44%). Both blue dye and isotope identified the SLN in 16 of 24 successful procedures (67%). Additional, nonsentinel nodes (mean, eight nodes) were removed in 17 of 24 patients (71%) and were negative in all cases. At a median followup of 13 months, no axillary recurrences have occurred. CONCLUSIONS: Reoperative SLN biopsy after earlier SLN biopsy or ALND is feasible in selected breast cancer patients and is more likely to succeed when fewer than 10 nodes were removed during the earlier procedure. Further study is required to better define the subset of patients in whom reoperative SLN biopsy can replace ALND.

Day to day treatment variations of accelerated partial breast brachytherapy using a multi-lumen balloon.

PURPOSE: To evaluate the variations of multi-lumen balloon (MLB)-based brachytherapy from simulation day to treatment day and their dosimetric impacts during accelerated partial breast irradiation (APBI). MATERIAL AND METHODS: A total of 42 CT images scanned from seven patients were evaluated with regards to daily variation due to of: 1) internal uncertainty: size and shape of balloon, seroma volume; 2) geometrical uncertainty-random: length of each catheter was measured for each fraction (total 70); 3) geometrical uncertainty-systematic: virtual systematic errors were tested by offsetting dwell positions. The original plans (as group A) had a mean value of 96.8% on V95 of the PTV_Eval. Plans were rerun (as group B) such that the mean value of the V95 was relaxed to 90.4%. By applying the reference plan to each daily CT image, variations of target coverage under different sources of error were evaluated. RESULTS: Shape and size of the balloon had means of < 1 mm decreased in diameter and < 0.4 cm(3) decreased in volume; the mean seroma volume increased by 0.2 cm(3). This internal variation has a mean of < 1% difference for both V90 and V95. The geometrical uncertainty made a mean deviation of 2.7 mm per root of sum of square. It caused the degradations of V90 and V95 by mean values of 1.0% and 1.2%, respectively. A systematic error of 3 mm and 4 mm would degrade both of V90 and V95 by 4% and 6%, respectively. The degradations on target coverage of the plans in group A were statistically the same as those in group B. CONCLUSIONS: Overall, APBI treatments with MLB based brachytherapy are precise from day to day. However, minor variation due to daily treatment uncertainties can still degrade tumor bed coverage to an unacceptable coverage when V95 of the original plan is close to 90%.

Results of MRI screening for breast cancer in high-risk patients with LCIS and atypical hyperplasia.

BACKGROUND: Magnetic resonance imaging (MRI) can detect breast cancer in high-risk patients, but is associated with a significant false-positive rate resulting in unnecessary breast biopsies. More data are needed to define the role of MRI screening for specific high-risk groups. We describe our experience with MRI screening in patients with atypical hyperplasia (AH) and lobular carcinoma in situ (LCIS). METHODS: We retrospectively reviewed data from our high-risk screening program prospective database for the period from April 1999 (when screening MRI was first performed at our institution) to July 2005. Patients with AH or LCIS demonstrated on previous surgical biopsy were identified. All patients underwent yearly mammography and twice yearly clinical breast examination. Additional screening MRI was performed at the discretion of the physician and patient. RESULTS: We identified 378 patients; 126 had AH and 252 had LCIS. Of these, 182 (48%) underwent one or more screening MRIs (mean, 2.6 MRIs; range, 1-8) during this period, whereas 196 (52%) did not. Those who had MRIs were younger (P < 0.001) with stronger family histories of breast cancer (P = 0.02). In MRI-screened patients, 55 biopsies were recommended in 46/182 (25%) patients, with 46/55 (84%) biopsies based on MRI findings alone. Cancer was detected in 6/46 (13%) MRI-generated biopsies. None of the six cancers detected on MRI were seen on recent mammogram. All six cancers were detected in five patients (one with bilateral breast cancer) with LCIS; none were detected by MRI in the AH group. Thus, cancer was detected in 5/135 (4%) of patients with LCIS undergoing MRI. The yield of MRI screening overall was cancer detection in 6/46 (13%) biopsies, 5/182 (3%) MRI-screened patients and 5/478 (1%) total MRIs done. In two additional MRI-screened patients, cancer was detected by a palpable mass in one, and on prophylactic surgery in the other and missed by all recent imaging studies. For 196 non-MRI-screened patients, 21 (11%) underwent 22 biopsies during the same period. Eight of 22 (36%) biopsies yielded cancer in seven patients. All MRI-detected cancers were stage 0-I, whereas all non-MRI cancers were stage I-II. CONCLUSION: Patients with AH and LCIS selected to undergo MRI screening were younger with stronger family histories of breast cancer. MRI screening generated more biopsies for a large proportion of patients, and facilitated detection of cancer in only a small highly selected group of patients with LCIS.

Unilateral postoperative chest wall radiotherapy in bilateral tissue expander/implant reconstruction patients: a prospective outcomes analysis.

BACKGROUND: Implant reconstruction has a major role to play in breast reconstruction, as some patients neither wish nor are suitable for autogenous reconstruction. The suitability of implant reconstruction in patients who may receive postoperative, adjuvant radiation therapy has not, however, been fully clarified. The purpose of this study was to evaluate complications, capsular contracture, aesthetic outcomes, and patient satisfaction in patients who have undergone bilateral tissue expander/implant reconstruction and unilateral, post exchange, adjuvant radiotherapy. In this study population, the effect of radiation can best be appreciated because the nonirradiated breast acts as a control. METHODS: A review of all bilateral tissue expander/implant reconstructions at a single cancer center was undertaken. Twelve patients who underwent bilateral expander/implant reconstruction and unilateral postexchange radiotherapy were eligible for participation. A prospective evaluation of complications, cosmesis, and patient satisfaction was performed. The evaluation of cosmesis and patient satisfaction was executed for 10 of the 12 patients, as two were dead at the time of follow-up. RESULTS: Mean follow-up was 23.5 months (range, 12 to 58.5 years). In 40 percent of patients, there was no discernible difference in capsular contracture between the irradiated and nonirradiated breasts. In 50 percent of patients, the irradiated breast demonstrated increased contracture by a single modified Baker grade. In 10 percent of patients, contracture of the irradiated breast was two modified Baker grades greater than that of the nonirradiated side (grade III versus grade I). CONCLUSION: For the majority of patients, the degree of capsular contracture was higher on the irradiated side, yet overall symmetry, aesthetic results, and patient satisfaction remained high. These data support the conclusion that immediate, bilateral breast reconstruction using tissue expansion and implants is an acceptable option for the subset of patients who may undergo unilateral, postexchange radiotherapy.

A prospective analysis of the effect of blue-dye volume on sentinel lymph node mapping success and incidence of allergic reaction in patients with breast cancer.

BACKGROUND: This study examined whether the volume of isosulfan blue dye used in sentinel lymph node (SLN) mapping in breast cancer is related to the SLN identification rate or to the incidence of allergic reactions. METHODS: From January 2001 to November 2002, 1728 breast cancer patients underwent 1832 SLN mapping procedures with the combined technique of intraparenchymal blue dye and intradermal radioisotope. Details of each procedure and all allergic reactions were prospectively recorded. Bilateral synchronous SLN procedures were considered as one dye exposure but as two distinct procedures for determining mapping success. Dye-only success was defined as the proportion of cases in which the SLN was identified by blue dye alone. Overall dye success was defined as the proportion of cases in which the SLN was identified by blue dye with or without isotope. RESULTS: When stratified by volume of blue dye, there were no significant differences in dye-only successes, overall dye successes, or mapping failures. Allergic reactions were documented in 31 (1.8%) of 1728 patients. Hypotensive reactions occurred in 3 (.2%) of 1728 patients; 2 (.1%) required pressor support. There was a nonsignificant trend toward fewer allergic reactions with smaller volumes of blue dye. CONCLUSIONS: In combined-technique SLN mapping protocols for breast cancer, using smaller volumes of blue dye may represent a means of optimizing the safety of the procedure without compromising its success.

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.

Sensory morbidity after sentinel lymph node biopsy and axillary dissection: a prospective study of 233 women.

BACKGROUND: We prospectively compared the sensory morbidity and lymphedema experienced after sentinel node biopsy (SLNB) and axillary dissection (ALND) over a 12-month period by using a validated instrument. METHODS: Patients undergoing breast-conserving therapy completed the Breast Sensation Assessment Scale (BSAS) at baseline and 3, 6, and 12 months after surgery. Repeated-measures analysis of variance was used to compare ALND and SLNB over the 12-month period. Upper- and lower-arm circumference measurements at baseline and 12 months were used to assess lymphedema. RESULTS: SLNB was associated with substantial sensory morbidity, although significantly less than ALND, over time on all four subscales and the summary score. A statistically significant improvement in sensory morbidity occurred for both groups in the first 3 months, with no further change thereafter. For both types of axillary surgery, younger patients had significantly higher BSAS scores than older patients. There was no significant difference in arm circumference between patients with SLNB and ALND at 12 months. CONCLUSIONS: Among women undergoing breast-conserving therapy, SLNB has significant sensory morbidity, although approximately half that of ALND. Sensory morbidity improves in the first 3 months after surgery, but patients continue to report sensory morbidity at 1 year. Longitudinal follow-up is required to further assess lymphedema.