Managing a small recurrence in the previously irradiated breast. Is there a second chance for breast conservation?

Over the past 30 years, lumpectomy and radiation therapy (breast-conservation therapy, or BCT) has been the preferred treatment for early-stage breast cancer. With accumulating follow-up, we have an ever-expanding pool of patients with history of an irradiated intact breast. Routine use of every-6-month or annual screening in this population has identified an emerging clinical dilemma with respect to managing a small recurrence or a second primary tumor in the treated breast. Most women diagnosed with a second cancer in a previously irradiated breast are advised to undergo mastectomy. More recently, with an improved understanding of the patterns of in-breast failure, and with advances in the delivery of conformal radiation dose there is an opportunity to reevaluate treatment alternatives for managing a small in-breast recurrence. A limited number of publications have reported on patient outcomes after a second lumpectomy and radiation therapy for this clinical scenario. In this report, we review the controversial subject of a second chance at breast conservation for women with a prior history of breast irradiation.

A pooled analysis of bone marrow micrometastasis in breast cancer.

BACKGROUND: We assessed the prognostic significance of the presence of micrometastasis in the bone marrow at the time of diagnosis of breast cancer by means of a pooled analysis. METHODS: We combined individual patient data from nine studies involving 4703 patients with stage I, II, or III breast cancer. We evaluated patient outcomes over a 10-year follow-up period (median, 5.2 years), using a multivariable piecewise Cox regression model. RESULTS: Micrometastasis was detected in 30.6 percent of the patients. As compared with women without bone marrow micrometastasis, patients with bone marrow micrometastasis had larger tumors and tumors with a higher histologic grade and more often had lymph-node metastases and hormone receptor-negative tumors (P<0.001 for all variables). The presence of micrometastasis was a significant prognostic factor with respect to poor overall survival and breast-cancer-specific survival (univariate mortality ratios, 2.15 and 2.44, respectively; P<0.001 for both outcomes) and poor disease-free survival and distant-disease-free survival during the 10-year observation period (incidence-rate ratios, 2.13 and 2.33, respectively; P<0.001 for both outcomes). In the multivariable analysis, micrometastasis was an independent predictor of a poor outcome. In the univariate subgroup analysis, breast-cancer-specific survival among patients with micrometastasis was significantly shortened (P<0.001 for all comparisons) among those receiving adjuvant endocrine treatment (mortality ratio, 3.22) or cytotoxic therapy (mortality ratio, 2.32) and among patients who had tumors no larger than 2 cm in diameter without lymph-node metastasis and who did not receive systemic adjuvant therapy (mortality ratio, 3.65). CONCLUSIONS: The presence of micrometastasis in the bone marrow at the time of diagnosis of breast cancer is associated with a poor prognosis.

Sentinel node positivity rates with and without frozen section for breast cancer.

BACKGROUND: Sentinel lymph node biopsy (SLNB) is used to detect breast cancer axillary metastases. Some surgeons send the sentinel lymph node (SLN) for intraoperative frozen section (FS) to minimize delayed axillary dissections. There has been concern that FS may discard nodal tissue and thus underdiagnose small metastases. This study examines whether evaluation of SLN by FS increases the false-negative rate of SLNB. METHODS: A retrospective analysis of SLNB from 659 patients was conducted to determine the frequency of node positivity among SLNB subjected to both FS and permanent section (PS) versus PS alone. Statistical analysis was performed by the chi(2) square test, and a logistic regression model was applied to estimate the effect of final node positivity between the two groups. RESULTS: FS was performed in 327 patients and PS was performed in all 659 patients. Among patients undergoing both FS and PS (n = 327), the final node positivity rate was 33.0% compared with 19.6% among patients undergoing PS alone (n = 332). After adjustment for patient age, tumor diameter, grade, and hormone receptor status in a multivariate logistic regression model, there remained an increased likelihood of final node positivity for patients undergoing both procedures relative to PS alone (adjusted odds ratio, 2.1; 95% confidence interval, 1.3-3.6; P = .005). CONCLUSIONS: There was a higher rate of SLN positivity in specimens evaluated by both FS and PS. Therefore, evaluating SLN by FS does not underdiagnose small metastases nor produce a higher false-negative rate. Intraoperative FS offers the advantage of less delayed axillary dissections.

The influence of additional surgical margins on the total specimen volume excised and the reoperative rate after breast-conserving surgery.

BACKGROUND: It is unclear whether the additional removal of breast tissue during breast-conserving therapy (BCT) for breast cancer beyond the standard lumpectomy reduces the incidence of inadequate microscopic margins found at pathological examination and subsequent reoperation. This study compares the reoperative rates after initial BCT in 3 groups of patients who underwent lumpectomy with complete resection of 4 to 6 additional margins, lumpectomy with selective resection of 1 to 3 additional margins, or standard lumpectomy. METHODS: Retrospective data were reviewed from 171 selected cases of BCT, from May 2000 to February 2006. Forty-five cases involved lumpectomy with complete resection of 4 to 6 additional margins; 77 involved lumpectomy with selective resection of 1 to 3 additional margins, whereas 49 involved standard lumpectomy. All samples underwent pathologic analysis of inked resection margins by permanent section. The 3 groups were compared for patient demographics, tumor size and histologic subtype, tumor stage, margin status, excised specimen volume, and eventual subsequent reoperation. Adequate surgical margin was defined as any negative margin greater than 2 mm. RESULTS: The group with complete resection of 4 to 6 additional margins had a subsequent reoperation rate of 17.7%, whereas the group with selective resection of 1 to 3 additional margins and the standard lumpectomy group had a subsequent reoperation rate of 32.5% and 38.7%, respectively, because of inadequate margins. The mean total excised specimen volume in the 3 groups was 129.19, 46.04, and 37.44 cm3, respectively. CONCLUSIONS: The complete resection of 4 to 6 additional margins during the initial BCT resulted in the lowest subsequent reoperation rate, and the largest total volume specimen excised among the 3 techniques studied.

Do bone marrow micrometastases correlate with sentinel lymph node metastases in breast cancer patients?

BACKGROUND: Sentinel lymph node biopsies (SLNB) are used to detect axillary metastases as an important prognostic indicator for breast cancer patients. Bone marrow micrometastases (BMM) have also been shown to predict prognosis. This study examines whether SLNB and BMM are associated. STUDY DESIGN: A retrospective analysis was performed on 124 stages I to III breast cancer patients treated with mastectomy or lumpectomy, SLNB, and bone marrow aspiration between 1997 and 2003. SLNB were examined for the presence of metastases by hematoxylin and eosin (H&E) stains and also by immunohistochemistry (IHC) for lymph nodes negative by H&E. The kappa statistic was used to evaluate the association (agreement) between SLNB and BMM. RESULTS: In this study population, 36 patients (29%) had micrometastases detected in their bone marrow, and 51 patients (41%) had positive sentinel lymph nodes. Of the patients with positive BMM (n = 36), 53% (19 of 36) had positive SLNB (14 of 19 by H&E and 5 of 19 by IHC). In patients with negative BMM (n = 88), 36% (32 of 88) had a positive SLNB (27 of 32 by H&E and 5 of 32 by IHC). The kappa statistic and associated 95% confidence interval indicated poor agreement between SLNB and BMM (kappa = 0.15; 95% CI = -0.03, 0.32). CONCLUSIONS: There was poor agreement between axillary metastases and micrometastases detected in the bone marrow. This study suggests that BMM and axillary metastases are not concordant findings in most patients.

Novel cell culture models for prevention of human breast cancer (Review).

Human breast cancer is a multifactorial, multistep disease wherein genetic, endocrine and dietary factors represent crucial regulators of initiation, promotion and progression. Preclinical investigations utilizing human breast carcinoma derived cell lines either in culture, or upon xenotransplantation, have provided valuable leads for molecular pathogenesis of cancer progression and also for novel therapeutic modalities. The mechanistic significance of genetic factors on early events of initiation/promotion, however, is dependent on extrapolation, and is therefore, equivocal. Human tissue derived explant culture/cell culture models utilizing non-involved target tissue at risk for carcinogenic transformation provide a novel approach that minimizes extrapolation for clinical relevance and thereby maximizes the translational impact. This report provides an overview of laboratory investigations focused on: i) development of the model, ii) optimization of mechanistic biomarker assays for carcinogenic transformation, and iii) validation of the model as a high throughput mechanistic screen for preclinical efficacy of natural phytochemicals.

Preventive efficacy of receptor class selective retinoids on HER-2/neu oncogene expressing preneoplastic human mammary epithelial cells.

Aberrant proliferation is an early-occurring event in vitro prior to tumorigenesis in vivo in the multistep process of carcinogenesis. Inhibition of aberrant proliferation therefore may represent a useful biomarker to evaluate the efficacy of chemopreventive agents. Retinoids have exhibited preventive efficacy in vitro and in vivo predominantly through the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). Clinically relevant biochemical and cellular mechanistic endpoints for chemopreventive effects of retinoids should provide novel biomarkers. The present study was designed to examine the preventive efficacy of natural retinoids, all-trans-retinoic acid (ATRA) and 9-cis-retinoic acid (9cisRA), and to identify the possible mechanisms for their effects using the HER-2/neu oncogene expressing preneoplastic human mammary epithelial 184-B5/HER cells. Seven-day treatment with ATRA and 9cisRA exhibited a dose-dependent growth inhibition. Long-term (21 days) treatment with IC20 doses of 50 nM ATRA and 100 nM 9cisRA inhibited anchorage-dependent colony forming efficiency by about 75.4% (p<0.01) and 84.9% (p<0.01), respectively. Cell cycle analysis revealed that a 24-h treatment with IC90 doses of 2 microM ATRA and 3 microM 9cisRA accumulates cells in the G0/G1 phase and inhibit S and/or G2/M phase of the cell cycle. ATRA and 9cisRA induced an 11-fold (p=0.03) and a 9-fold (p=0.04) increase in subG0/G1 (apoptotic) population relative to the solvent control, respectively. ATRA and 9cisRA induced 77% (p=0.01) and 51% (p=0.02) decrease in tyrosine kinase immunoreactivity, respectively. Similarly, the two retinoids caused almost a 50% (p=0.01) down-regulation of Bcl-2 immunoreactivity. Western blot analysis revealed that ATRA induced an increase in RARbeta expression and a decrease in RARgamma expression, while 9cisRA down-regulated RXRalpha expression. These data demonstrate that ATRA and 9cisRA may inhibit HER-2/neu induced aberrant proliferation in part by retarding cell cycle progression, down-regulating HER-2/neu-mediated signal transduction and inducing Bcl-2-dependent apoptosis through a retinoid receptor-mediated mechanism.

Pathological examination of sentinel lymph node in breast cancer: potential problems and possible solutions.

Sentinel lymph node (SLN) biopsy has emerged during the last few years as a viable option for staging the axilla in the treatment of breast carcinoma. This procedure can potentially identify patients who would be helped by full axillary lymph node dissection (the SLN-positive cases), and those who would not (the SLN-negative cases). Review of the literature confirms the promise of SLN; however, the possible problems in the pathological handling of SLN, including the microscopic misinterpretation of benign structures and "spurious" immunohistochemical staining, need wider recognition.

Comparative study of the invasiveness of Salmonella serotypes Typhimurium, Choleraesuis and Dublin for Caco-2 cells, HEp-2 cells and rabbit ileal epithelia.

Patterns of invasiveness of Salmonella serotypes Typhimurium, Choleraesuis and Dublin in Caco-2 cells (without centrifugation) were compared with previously published studies of the rabbit ileal invasion assay (RIIA) and (where relevant) a HEp-2 cell invasion assay. Optimal conditions for the use of Caco-2 cell monolayers in bacterial invasion assays were defined. Centrifuge-assisted attachment of bacteria to cells was not used routinely as this increased the invasiveness of known hypo-invasive strains and detachment of Caco-2 cells. Inocula with too high bacterial numbers resulted in rapid acidification of media and detachment of the monolayers. The invasiveness of Typhimurium strains TML, WAKE, WII8, LT7, SL1027 and M206 in Caco-2 cells reflected that seen in the RIIA. The invasiveness of Choleraesuis strain A50 was similar to that in the RIIA except that bacteria grown at 37 degrees C and used without storage at 4 degrees C were slightly more invasive than those grown at 37 degrees C and stored at 4 degrees C before use. Dublin strain 3246 showed no apparent temperature-regulated invasiveness in Caco-2 cells, in contrast to the results observed in the RIIA. Dublin strain 3246 did not cleave tight junctions in the Caco-2 cell monolayer as it did in rabbit ileal epithelia both in vitro and in vivo. Three TnphoA insertion LPS mutants of Typhimurium TML were uniformly hypo-invasive in both Caco-2 cells and the RIIA; in contrast, they were differentially invasive in HEp-2 cells. Three smooth TnphoA insertion mutants of Typhimurium TML (invH, invG and pagC) were hypo-invasive in both the Caco-2 and HEp-2 cell invasion assays but not in the RIIA.

Invasiveness of Salmonella serotypes Typhimurium, Choleraesuis and Dublin for rabbit terminal ileum in vitro.

Ten recent clinical isolates of Salmonella serotype Typhimurium from man that were tested for their invasiveness in rabbit ileal explants in vitro, were compared with Typhimurium strain TML, a well-characterised invasive strain isolated from a case of human gastro-enteritis. Nine of the 10 strains showed invasiveness that was comparable to that of strain TML. One isolate (GM3) was apparently substantially less invasive; electron microscopy showed this strain to be histotoxic - the probable reason for its reduced recovery from ileal mucosa and thus apparent 'low' invasiveness. Salmonella serotype Choleraesuis strain A50, isolated from a case of systemic salmonellosis in pigs, and serotype Dublin strain 3246, isolated from a case of systemic salmonellosis in calves, were also examined. Dublin strain 3246, when grown at 37 degrees C and used immediately in the invasion assay, damaged the mucosa in a manner similar to that of Typhimurium strain GM3, whereas Dublin strain 3246 grown at 37 degrees C and stored overnight at 4 degrees C did not. This was reflected in an apparently lower invasiveness of freshly grown organisms compared with that of organisms stored at 4 degrees C. In contrast, the histotoxicity of Typhimurium strain GM3 was not affected by storage at 4 degrees C. When stored at 4 degrees C, the levels of invasiveness of Choleraesuis strain A50 and Dublin strain 3246 were not significantly different from each other or from Typhimurium strain TML.

A histotoxin produced by Salmonella.

Salmonella Typhimurium strain GM3, known to be histotoxic for explants of terminal rabbit ileum in vitro, produces similar lesions in vitro when sterile filtrates, obtained from live organisms after interaction with gut explants in vitro, are used and when rabbit ligated ileal loops are challenged with live organisms. Epithelial damage occurs rapidly, within 2 h of adding organisms or sterile filtrates. This evidence is construed in terms of a secreted salmonella histotoxin that causes epithelial damage, detaching enterocytes which rapidly degenerate into spheroid cells devoid of microvilli. Typhimurium strain GM3 invades ileal mucosa and bacteria are found in the subepithelial tissues. After 12 h, bacteria were seen to be expelled from infected villi in a manner similar to that seen in non-histotoxic infection with Typhimurium strain TML.

Myofibroblastoma in the Irradiated Breast.

Myofibroblastoma after wide excision and radiation therapy for intraductal (duct carcinoma in situ) carcinoma is reported. Myofibroblastoma is a benign tumor, largely composed of myofibroblasts arranged in fascicular clusters with interspersed bands of hyalinized collagen, which is well circumscribed and occurs predominantly in men. This is the first documented instance of a postradiation myofibroblastoma of the breast.

Early-stage breast cancer treated with 3-week accelerated whole-breast radiation therapy and concomitant boost.

PURPOSE: To report early outcomes of accelerated whole-breast radiation therapy with concomitant boost. METHODS AND MATERIALS: This is a prospective, institutional review board-approved study. Eligibility included stage TisN0, T1N0, and T2N0 breast cancer. Patients receiving adjuvant chemotherapy were ineligible. The whole breast received 40.5 Gy in 2.7-Gy fractions with a concomitant lumpectomy boost of 4.5 Gy in 0.3-Gy fractions. Total dose to the lumpectomy site was 45 Gy in 15 fractions over 19 days. RESULTS: Between October 2004 and December 2010, 160 patients were treated; stage distribution was as follows: TisN0, n = 63; T1N0, n = 88; and T2N0, n = 9. With a median follow-up of 3.5 years (range, 1.5-7.8 years) the 5-year overall survival and disease-free survival rates were 90% (95% confidence interval [CI] 0.84-0.94) and 97% (95% CI 0.93-0.99), respectively. Five-year local relapse-free survival was 99% (95% CI 0.96-0.99). Acute National Cancer Institute/Common Toxicity Criteria grade 1 and 2 skin toxicity was observed in 70% and 5%, respectively. Among the patients with ≥ 2-year follow-up no toxicity higher than grade 2 on the Late Effects in Normal Tissues-Subjective, Objective, Management, and Analytic scale was observed. Review of the radiation therapy dose-volume histogram noted that ≥ 95% of the prescribed dose encompassed the lumpectomy target volume in >95% of plans. The median dose received by the heart D05 was 215 cGy, and median lung V20 was 7.6%. CONCLUSIONS: The prescribed accelerated schedule of whole-breast radiation therapy with concomitant boost can be administered, achieving acceptable dose distribution. With follow-up to date, the results are encouraging and suggest minimal side effects and excellent local control.

Effectiveness of a noninvasive digital infrared thermal imaging system in the detection of breast cancer.

BACKGROUND: Digital infrared thermal imaging (DITI) has resurfaced in this era of modernized computer technology. Its role in the detection of breast cancer is evaluated. METHODS: In this prospective clinical trial, 92 patients for whom a breast biopsy was recommended based on prior mammogram or ultrasound underwent DITI. Three scores were generated: an overall risk score in the screening mode, a clinical score based on patient information, and a third assessment by artificial neural network. RESULTS: Sixty of 94 biopsies were malignant and 34 were benign. DITI identified 58 of 60 malignancies, with 97% sensitivity, 44% specificity, and 82% negative predictive value depending on the mode used. Compared to an overall risk score of 0, a score of 3 or greater was significantly more likely to be associated with malignancy (30% vs 90%, P < .03). CONCLUSION: DITI is a valuable adjunct to mammography and ultrasound, especially in women with dense breast parenchyma.

Do additional shaved margins at the time of lumpectomy eliminate the need for re-excision?

BACKGROUND: Most women diagnosed with breast cancer undergo breast-conservation surgery. Re-excision rates for positive margins have been reported to be greater than 50%. The purpose of our study was to determine if removing additional shaved margins from the lumpectomy cavity at the time of lumpectomy reduces re-excisions. METHODS: A retrospective study was performed on 125 women who had undergone lumpectomy with additional shaved margins taken from the lumpectomy cavity. Pathology reports were reviewed for tumor size and histology, lumpectomy and additional margin status, and specimen and margin volume. RESULTS: If additional margins were not taken, 66% would have required re-excision. Because of taking additional shaved margins, re-excision was eliminated in 48%. CONCLUSION: Excising additional shaved margins at the original surgery reduced reoperations by 48%. There is a balance between removing additional margins and desirable cosmesis after breast-conservation surgery. The decision to take extra margins should be based on the surgeon's judgment.

Does oncotype DX recurrence score affect the management of patients with early-stage breast cancer?

BACKGROUND: Oncotype DX is a 21-gene assay that calculates a risk of distant recurrence in women with estrogen-receptor-positive, lymph node-negative breast cancer. The purpose of this study was to determine whether the results of Oncotype DX influence the decision to administer chemotherapy. METHODS: A retrospective study was performed on 85 consecutive patients with estrogen-receptor-positive, lymph node-negative breast cancer who had an Oncotype DX recurrence score (RS) obtained. Tumor size, tumor grade, and treatment were then compared within each risk category. Statistical analysis was performed using STATA software. RESULTS: Tumors that were high grade and Her-2/neu positive more frequently had a high RS. Treatment was changed as a result of Oncotype DX in 44% of patients. CONCLUSIONS: Oncotype DX RS is significantly related to tumor grade and Her2/neu status. In this study, the treatment of 44% of patients was altered as a consequence of Oncotype DX RS.

William Stewart Halsted: his life and contributions to surgery.

William Stewart Halsted was a pioneer of surgery in the USA and made many wide-ranging contributions, including the surgical treatment of breast cancer. He changed the training of surgeons from a disorganised apprenticeship to the residency training programmes used today. Halsted's research developed a better understanding of surgically amenable disease and a multitude of new techniques and operations. Over a 40-year career, beginning in New York and continuing at Johns Hopkins University Hospital in Baltimore, he endured a terrible struggle resulting from an accidental addiction, acquired in the course of his research. Despite this, his legacy to medicine and human health is one of the greatest left by any individual surgeon in history and remains an inspiration today.

Concurrent invasive ductal carcinoma and chronic lymphocytic leukemia manifesting as a collision tumor in breast.

Collision tumors are rare clinical entities in which two histologically distinct tumor types show involvement in the same site. The occurrence of these tumors in the breast is extremely rare. Here, we present a case of a patient with both invasive ductal carcinoma and chronic lymphocytic leukemia in the breast. Wide excision with sentinel lymph node biopsy revealed palpably abnormal lymph nodes negative for breast carcinoma on frozen section. Histopathological examination of these lymph nodes showed extensive involvement by lymphoma and review of the breast specimen demonstrated the same lymphoma at the periphery of the ductal carcinoma. We review the literature and discuss possible etiologies for the dual presentation of both cancers.