Identification of breast cancer DNA methylation markers optimized for fine-needle aspiration samples.

BACKGROUND: Random periareolar fine-needle aspiration (RP-FNA) is increasingly used in trials of breast cancer prevention for biomarker assessments. DNA methylation markers may have value as surrogate endpoint biomarkers, but this requires identification of biologically relevant markers suitable for paucicellular, lymphocyte-contaminated clinical samples. METHODS: Unbiased whole-genome 5-aza-2'-deoxycytidine (5AZA)-induced gene expression assays, followed by several phases of qualitative and quantitative methylation-specific PCR (MSP) testing, were used to identify novel breast cancer DNA methylation markers optimized for clinical FNA samples. RESULTS: The initial 5AZA experiment identified 453 genes whose expression was potentially regulated by promoter region methylation. Informatics filters excluded 273 genes unlikely to yield useful DNA methylation markers. MSP assays were designed for 271 of the remaining genes and, ultimately, 33 genes were identified that were differentially methylated in clinical breast cancer samples, as compared with benign RP-FNA samples, and never methylated in lymphocytes. A subset of these markers was validated by quantitative multiplex MSP in extended clinical sample sets. Using a novel permutation method for analysis of quantitative methylation data, PSAT1, GNE, CPNE8, and CXCL14 were found to correlate strongly with specific clinical and pathologic features of breast cancer. In general, our approach identified markers methylated in a smaller subpopulation of tumor cells than those identified in published methylation array studies. CONCLUSIONS: Clinically relevant DNA methylation markers were identified using a 5AZA-induced gene expression approach. IMPACT: These breast cancer-relevant, FNA-optimized DNA methylation markers may have value as surrogate endpoint biomarkers in RP-FNA studies.

Outcomes of delays in time to treatment in triple negative breast cancer.

BACKGROUND: Compared with other breast cancer subtypes, triple negative breast cancers (TNBC) are associated with higher recurrence rates and worse survival. Because of the aggressive nature of TNBC, outcomes may be more sensitive to delays in time to treatment. This study evaluates whether delays from diagnosis to initial treatment in TNBC impacts survival or locoregional recurrence (LRR). METHODS: Retrospective review of TNBC patients treated between January 2004 and January 2011 at an academic center was performed. Data collected included demographics, pathology, treatment, recurrence, and survival. Interval to treatment was defined as days from pathologic diagnosis to first local or systemic treatment. The t test, Cox regression, and Kaplan-Meier analyses were used to evaluate impact of time to treatment on overall survival and LRR. RESULTS: Median follow-up was 40 months for 301 TNBC patients. Mean interval to treatment was 46 ± 2 days. Higher initial stage yielded worse survival (p < .0001). Interval to treatment did not impact overall survival (p = .24), although there was a trend toward worse survival with delays of >90 days (p = .06). LRR was seen in 20 patients (7 %). Median time to recurrence was 15 months. Time to treatment was 38 ± 6 days for patients with LRR versus 44 ± 2 days without a recurrence (p = .37). Short delay in time to treatment did not impact LRR (p = .54). CONCLUSIONS: In TNBC, a short delay from pathologic diagnosis to initial treatment does not appear to adversely affect survival or LRR. Appropriate time to perform evaluations such as genetic testing, imaging, or additional consultation can be taken to guide optimal treatment options.

Influence of surgical technique on mastectomy and reexcision rates in breast-conserving therapy for cancer.

Introduction. Breast conserving surgery (BCS) requires tumor excision with negative margins. Reexcision rates of 30-50% are reported. Ultrasound localization, intraoperative margin pathology, and specimen mammography have reduced reexcisions, but require new equipment. Cavity shave margin (CSM) is a technique, utilizing existing equipment, that potentially reduces reexcision. This study evaluates CSM reexcision impact. Methods. 522 cancers treated with BCS were reviewed. Patients underwent standard partial mastectomy (SPM) or CSM. Data collected included demographics, pathology, and treatments. Results. 455 SPMs were compared to 67 CSMs. Analysis revealed no differences in pathology, intraductal component, or neoadjuvant chemotherapy. Overall reexcision rate = 43%. Most reexcisions were performed for DCIS at margin. SPMs underwent 213 reexcisions (46.8%), versus 16/67 (23.9%) CSMs (P = 0.0003). Total mastectomy as definitive procedure was performed after more SPMs (P = 0.009). Multivariate analysis revealed CSM, % DCIS, tumor size, and race to influence reexcisions. Conclusions. CSM is a technique that reduces reexcisions and mastectomy rates.

Volume of excision and cosmesis with routine cavity shave margins technique.

BACKGROUND: Cavity shave margin (CSM) removal is a surgical technique that reduces re-excision rates. One criticism of this technique has been that negative margins are obtained primarily as a result of higher volumes of tissue removed. This study evaluates the volume of tissue removed in a group that underwent CSM versus one that underwent standard partial mastectomy (SPM) and explores cosmetic outcomes. METHODS: Single-institution retrospective review identified 533 patients with a diagnosis of breast cancer who underwent PM. Matched pair analysis of 72 patients who had undergone PM with CSM versus 72 who had undergone SPM was performed. Volumes were calculated from dimensions in the pathology report. A subgroup was analyzed by a multidisciplinary panel for cosmetic outcome using the Harvard Breast Cosmesis Grading Scale. RESULTS: Mean tumor size in the CSM group was 1.52 versus 1.51 cm(3) in the SPM (P = 0.8073). Mean total volume of tissue excised with CSM was lower than that in the SPM group. Mean volume of excision with CSM was 80.66 and 165.1 cm(3) in the SPM group (P = 0.0005). Patients undergoing CSM required fewer re-excisions than the SPM group: 13 (18.1%) versus 25 (34.6%) (P = 0.03). Mean score for cosmesis was 2.3 in the CSM group and 3.0 for SPM (P = 0.0004). CONCLUSIONS: CSM decreases the need for re-excision. Total tissue volume excised is lower in patients who undergo CSM, and cosmetic results appear to be improved. This approach should be considered for all patients undergoing PM.

Axillary lymph node dissection for breast cancer utilizing Harmonic Focus®.

BACKGROUND: For patients with axillary lymph node metastases from breast cancer, performance of a complete axillary lymph node dissection (ALND) is the standard approach. Due to the rich lymphatic network in the axilla, it is necessary to carefully dissect and identify all lymphatic channels. Traditionally, these lymphatics are sealed with titanium clips or individually sutured. Recently, the Harmonic Focus®, a hand-held ultrasonic dissector, allows lymphatics to be sealed without the utilization of clips or ties. We hypothesize that ALND performed with the Harmonic Focus® will decrease operative time and reduce post-operative complications. METHODS: Retrospective review identified all patients who underwent ALND at a teaching hospital between January of 2005 and December of 2009. Patient demographics, presenting pathology, treatment course, operative time, days to drain removal, and surgical complications were recorded. Comparisons were made to a selected control group of patients who underwent similar surgical procedures along with an ALND performed utilizing hemostatic clips and electrocautery. A total of 41 patients were included in this study. RESULTS: Operative time was not improved with the use of ultrasonic dissection, however, there was a decrease in the total number of days that closed suction drainage was required, although this was not statistically significant. Complication rates were similar between the two groups. CONCLUSION: In this case-matched retrospective review, there were fewer required days of closed suction drainage when ALND was performed with ultrasonic dissection versus clips and electrocautery.

Impact of routine cavity shave margins on breast cancer re-excision rates.

PURPOSE: Breast-conserving therapy (BCT) is an accepted method of treating early breast cancer. We hypothesized that routine excision of additional cavity shave margins (CSM) at time of initial partial mastectomy reduces the need for additional surgery. METHODS: A single-institution retrospective review was performed of women, 18 years or older, with a new diagnosis of breast cancer who underwent partial mastectomy between 1 January 2004 and 1 October 2009. Five hundred thirty-three charts were reviewed. Of those, 69 patients underwent CSM at time of initial operation. These 69 patients were matched with patients who had undergone partial mastectomy without CSM by tumor size, presence of extensive intraductal component, and primary histology. RESULTS: The two groups were well matched for age, nuclear grade, associated lymphovascular invasion (LVI), receptor status, and multifocality. We found that 31.9% (44/138) required return to the operating room (OR) for re-excision of margins. Rate of return to the OR was 21.7% (15/69) in the CSM group and 42.0% (29/69) in the matched group (p = 0.011). Multivariate analysis found factors significantly associated with need for additional operation included lack of CSM (odds ratio 9.2, 95% CI 2.8-30.5, p = 0.0003), larger extent of intraductal component (odds ratio 7.0, 95% CI 1.8-27.0, p = 0.005), and lack of directed re-excision (odds ratio 6.4, 95% CI 1.7-25.1, p = 0.007). CONCLUSIONS: CSM at time of initial partial mastectomy decreases rate of re-excision by as much as ninefold. CSM should be considered at time of initial operation to reduce the need for subsequent reoperation.

Delays in time to treatment and survival impact in breast cancer.

BACKGROUND: Time interval from diagnosis of breast cancer to treatment has been promulgated as one factor that can be used to evaluate cancer care quality. It remains controversial, however, whether a delay to treatment impacts survival. The purpose of this study was to evaluate whether delays from diagnosis to initial treatment in breast cancer impacts survival. MATERIALS AND METHODS: A retrospective review of patients undergoing breast cancer treatment between August 2005 and December 2008 in a comprehensive, multidisciplinary breast oncology program was undertaken. Two hospital systems were included: a county hospital (CH) treating a primarily minority, indigent population and a university hospital (UH) treating a primarily Caucasian, insured population. Interval to treatment, calculated from date of diagnosis to surgery, chemotherapy, or radiation treatment, and overall survival was compared between the two groups. RESULTS: A total of 1337 patients were included; 634 patients were treated in the CH and 703 in the UH. Interval to treatment was longer in the CH compared with the UH (53.4 ± 2.0 vs 33.2 ± 1.2 days; mean ± standard error of the mean [SEM], P < .0001). Patients treated at the CH had overall worse survival (P = .02); however, this difference did not hold true when controlled for stage. Additionally, when time to treatment was analyzed as an individual variable for all patients, there was no impact on survival. CONCLUSIONS: Interval from diagnosis to treatment of breast cancer within the same cancer center was longer at the CH than the UH. There was, however, no effect on overall survival. Time to treatment may not be a meaningful indicator of cancer care quality.

Experience with seed localization for nonpalpable breast lesions in a public health care system.

BACKGROUND: Seed localization uses a radioactive source to identify nonpalpable breast lesions for excision; it is an emerging alternative to wire localization (WL). Previous single health system studies report decreased rates of re-excision and improved patient convenience with this technique. This study is the first to implement this procedure in a public health care delivery system composed of a primarily minority and low-income population. MATERIALS AND METHODS: A multidisciplinary team was formed to create a protocol for breast seed localization (BSL) and monitor the results. After 50 seed localizations were successfully completed, a retrospective matched-pair analysis with patients who had undergone WL during the same period was performed. RESULTS: Overall experience with the BSL protocol is reviewed, along with the occurrence of a seed loss. Processes necessary to reactivate the BSL protocol and prevent future losses are delineated. BSL is associated with decreased rates of re-excision and can be successfully implemented in a public health care system. CONCLUSIONS: BSL is an attractive alternative to WL in a high-volume, county-based population. It allows increased efficiency in the operating room and has a low rate of complications. Cautionary measures must be taken to ensure proper seed chain of custody to prevent seed loss.

Late presentation of intestinal malrotation: an argument for elective repair.

BACKGROUND: Midgut malrotation most commonly presents in young children. This diagnosis is not often entertained in the adolescent or adult with abdominal complaints. We reviewed our experience with this subset of malrotation patients. METHODS: A retrospective review of medical records from adolescent or adult patients identified with a diagnosis of anomaly of intestinal fixation or malrotation, who were treated within our health system between 1993 and 2004. RESULTS: A total of 33 patients were diagnosed with malrotation and treated with Ladd's procedure. Acute abdominal pain was present in 50%, and chronic complaints were present in the other patients. Initial work-up included computed tomography (CT) scan (28%), upper gastrointestinal (UGI) study (38%), and plain films (47%) Postoperative complications occurred more frequently in patients that were operated on emergently (60%) than in those that underwent elective surgery (22%; p = 0.04). CONCLUSIONS: This large case series of intestinal malrotation in the nonpediatric age group suggests that Ladd's procedure can be performed very safely. Moreover, the results suggest that patients with known malrotation should have Ladd's procedure performed electively rather than urgently.