Determinants of short and long term outcomes in patients undergoing immediate breast reconstruction following neoadjuvant chemotherapy.

BACKGROUND: We evaluated oncologic outcomes and complications of skin-sparing mastectomy (SSM) and nipple-sparing mastectomy (NSM) with immediate reconstruction (IR) after neoadjuvant chemotherapy (NAC) in patients with early-stage and locally advanced breast cancer (BC). METHODS: BC patients from 2000 to 2014 treated with NAC followed by SSM/NSM and IR were reviewed. Patient demographics, tumor characteristics, NAC response, complications, and recurrence were analyzed. RESULTS: Two hundred sixty-nine patients with 280 BCs were treated with NAC followed by SSM (94%) or NSM (6%) with IR. Median age was 47 (26-72) years with a median follow-up of 45 months. Pathologic complete response (pCR) was noted in 49 (17.5%) cases. Overall 30-day complication rate was 13.2%. Variables associated with complications included BMI (P < 0.0001), tobacco use (P = 0.015), and adjuvant radiation (P = 0.025). Local-regional recurrence was 3.2% and metastatic recurrence was 13.2%. Variables predicting recurrence risk were pre-NAC tumor size (P < 0.001), residual tumor size (P = 0.002), Grade III (P = 0.002), HER-2 negative (P = 0.025), pre-NAC nodal disease (P = 0.05), and lack of pCR (P = 0.045). CONCLUSION: Following NAC, risk factors for complications in patients undergoing SSM/NSM with IR are high BMI, smoking, and adjuvant XRT. SSM/NSM following NAC is associated with excellent local control. These data support expanding the indications for NSM/SSM to include patients receiving NAC.

Immediate Reconstruction in Inflammatory Breast Cancer: Challenging Current Care.

BACKGROUND: Inflammatory breast cancer (IBC) is an aggressive disease that is treated with trimodality therapy consisting of neoadjuvant chemotherapy, surgery, and post-mastectomy radiation therapy (PMRT). Traditionally, modified radical mastectomy without reconstruction has been the operation of choice for patients with IBC due to fears of high rates of margin positivity, risk of local recurrence, and the need for PMRT. METHODS: A retrospective review was performed to evaluate women with IBC at our institution from 2006 to 2014 who completed trimodality therapy. Patients were identified as undergoing reconstruction or no reconstruction (NR), with reconstruction being further classified as immediate (IR) if reconstruction occurred at the initial surgery, or delayed (DR) if initial reconstruction occurred after PMRT. RESULTS: Sixty women with IBC were identified using inclusion criteria. The median follow-up was 2.3 years (range 1.4-4.6). Patients with IR had a statistically significant increased risk (p = 0.006) in postoperative complication rates compared with DR (0 %) and NR (2.6 %). Two patients had positive skin margins on final pathology (one IR, one NR), with both eventually having recurrence. Time to PMRT was delayed 10 days in patients with IR compared with those without IR. No statistically significant difference in recurrence rates was observed (p = 0.86) when comparing patients with IR and those with NR, and no difference in survival was observed between patients who had reconstruction and those without (p = 0.91). CONCLUSION: Performing IR with mastectomy for IBC is associated with increased complications, but is not associated with decreased survival or increased recurrence in selected patients. IR in selected IBC patients can facilitate successful breast reconstruction.

Fertility in Women of Reproductive Age After Breast Cancer Treatment: Practice Patterns and Outcomes.

BACKGROUND: Breast cancer is the most frequently occurring cancer in women of reproductive age, and systemic treatments may adversely affect childbearing plans. Use of assisted reproductive technologies and therapies for ovarian protection improve fertility prospects. We evaluated whether patients had a documented fertility discussion (FD) with their oncology physician prior to therapy, what options were chosen, and if pregnancy was achieved. METHODS: A retrospective chart review from 2006 to 2014 was performed to evaluate women aged 40 years and younger who were diagnosed with breast cancer and treated with chemotherapy and/or antihormonal therapy. Patient demographics, treatment regimens, presence or absence of FD, in vitro fertilization (IVF) consultation, gonadotropin-releasing hormone (GnRH) agonist use, and subsequent successful pregnancy were analyzed. RESULTS: Among 303 patients meeting the inclusion criteria, 80 (26 %) had an FD with their physician documented; 71 of these 80 women (89 %) sought further fertility consultation and options. Sixteen (20 %) women were prescribed a GnRH agonist only for ovarian protection during chemotherapy, 50 (63 %) underwent IVF consultation only, and 5 (6 %) had both a GnRH agonist prescribed and an IVF consultation. The overall pregnancy rate was 7 % at a mean of 3 years post breast cancer treatment. Pregnancy after treatment was more common among those pursuing IVF consultation or prescribed a GnRH agonist. CONCLUSIONS: In treating young breast cancer patients, it is important to assess fertility desire, discuss treatment risks relating to fertility, and discuss preservation options. Although not every woman in this group desired pregnancy, 71/80 (89 %) women having a documented FD sought further fertility consultation and options.

A common copy-number breakpoint of ERBB2 amplification in breast cancer colocalizes with a complex block of segmental duplications.

INTRODUCTION: Segmental duplications (low-copy repeats) are the recently duplicated genomic segments in the human genome that display nearly identical (> 90%) sequences and account for about 5% of euchromatic regions. In germline, duplicated segments mediate nonallelic homologous recombination and thus cause both non-disease-causing copy-number variants and genomic disorders. To what extent duplicated segments play a role in somatic DNA rearrangements in cancer remains elusive. Duplicated segments often cluster and form genomic blocks enriched with both direct and inverted repeats (complex genomic regions). Such complex regions could be fragile and play a mechanistic role in the amplification of the ERBB2 gene in breast tumors, because repeated sequences are known to initiate gene amplification in model systems. METHODS: We conducted polymerase chain reaction (PCR)-based assays for primary breast tumors and analyzed publically available array-comparative genomic hybridization data to map a common copy-number breakpoint in ERBB2-amplified primary breast tumors. We further used molecular, bioinformatics, and population-genetics approaches to define duplication contents, structural variants, and haplotypes within the common breakpoint. RESULTS: We found a large (> 300-kb) block of duplicated segments that was colocalized with a common-copy number breakpoint for ERBB2 amplification. The breakpoint that potentially initiated ERBB2 amplification localized in a region 1.5 megabases (Mb) on the telomeric side of ERBB2. The region is very complex, with extensive duplications of KRTAP genes, structural variants, and, as a result, a paucity of single-nucleotide polymorphism (SNP) markers. Duplicated segments are varied in size and degree of sequence homology, indicating that duplications have occurred recurrently during genome evolution. CONCLUSIONS: Amplification of the ERBB2 gene in breast tumors is potentially initiated by a complex region that has unusual genomic features and thus requires rigorous, labor-intensive investigation. The haplotypes we provide could be useful to identify the potential association between the complex region and ERBB2 amplification.

The 76-gene signature defines high-risk patients that benefit from adjuvant tamoxifen therapy.

PURPOSE: To assess the benefit from adjuvant systemic tamoxifen therapy in breast cancer risk groups identified by the previously established prognostic 76-gene signature. METHODS: In 300 lymph node-negative (LNN), estrogen receptor-positive (ER+) breast cancer patients (136 treated with adjuvant tamoxifen, 164 having received no systemic adjuvant therapy), distant metastasis-free survival (DMFS) as a function of the 76-gene signature was determined in a multicenter fashion. RESULTS: In 136 tamoxifen-treated patients, the 76-gene signature identified a group of patients with a poor prognosis [hazard ratio (HR), 4.62; P = 0.0248]. These patients showed a 12.3% absolute benefit of tamoxifen in 10-year DMFS (HR, 0.52; P = 0.0318) compared with untreated high-risk patients. This represented a 71% increase in relative benefit compared with the 7.2% absolute benefit observed for all 300 patients without using the gene signature. In the low-risk group there was no significant 10-year DMFS benefit of tamoxifen. CONCLUSIONS: The 76-gene signature defines high-risk patients who benefit from adjuvant tamoxifen therapy. Although we did not study the value of chemotherapy in this study, low-risk patients identified by the 76-gene signature have a prognosis good enough that chemotherapy would be difficult to justify. The prognosis of these patients is sufficiently good, in fact, that a disease-free benefit for tamoxifen therapy is difficult to prove, though benefits in terms of loco-regional relapse and a reduction in risk for contralateral breast cancer might justify hormonal therapy in these patients.

The importance of preoperative breast MRI for patients newly diagnosed with breast cancer.

The use of preoperative breast magnetic resonance imaging (bMRI) for patients newly diagnosed with breast cancer has been criticized for increasing the number of therapeutic mastectomies performed, as well as increasing the cost of treatment. The purpose of this report is to examine one surgeon's practice and to describe the MRI findings for patients with breast cancer to determine if those findings changed the therapeutic options for those patients in. Data were collected prospectively between August 2003 and January 2006 for patients newly diagnosed with breast cancer. Diagnoses were made by core biopsy or fine-needle aspiration; all lesions were intact at the time of MRI. Twenty-five percent of patients were found to have previously occult, but suspicious lesions on MRI that required additional diagnostic evaluation, including ultrasound, core biopsy, excisional biopsy, or any combination; for approximately half of these patients a separate cancer was confirmed. For most of these patients, the new lesion was ipsilateral and multicentric, and most required mastectomy. For the remaining 75% of patients, MRI confirmed the index lesion was the only area of concern, and appropriate surgical treatment was completed. Preoperative bMRI for patients newly diagnosed with breast cancer identified previously occult and separate tumors in 13% of patients, resulting in surgical treatment change for many.

Mammary ductoscopy and ductal washings for the evaluation of patients with pathologic nipple discharge.

The majority of breast diseases result from lesions of the ductal epithelium. Mammary ductoscopy allows for visualization of intraductal abnormalities, and ductoscopic lavage provides thousands of cells for analysis. We reviewed our experience of 89 cases of patients with pathologic nipple discharge (PND) undergoing ductoscopy-directed duct excision and collection of ductal washings. Patients undergoing ductoscopy-directed duct excision with ductal washings had an 88% abnormal pathology rate. Most abnormalities were benign (71% papillomas), but the atypia rate for this group was 62%. The combination of visualization and pathologic analysis of washings provided the highest predictive value for the diagnosis of papilloma. Cellular yields for this technique were excellent with most specimens yielding >5,000 epithelial cells per high powered field and with evaluable ductal cells in 82% of specimens. Mammary ductoscopy offers the advantage of a high lesion localization rates with intraoperative guidance. The most accurate tool was the combination of ductal washings and ductoscopic visualization, but preoperative use of these techniques is not helpful in most cases. Greater than 90% of patients with PND are found to have a lesion on pathologic examination when using this technique for directed duct excision. Of interest, ductal washings obtained from symptomatic patients with benign diseases are often atypical.

Guidelines for using breast magnetic resonance imaging to evaluate implant integrity.

The purpose of this report was to review our experience with using breast magnetic resonance imaging to evaluate breast implant integrity and to offer a decision tree to assist physicians in managing these patients. Data were available for 81 patients with 146 implants placed either unilaterally or bilaterally for either cosmesis or breast reconstruction. The chief complaint for a majority of patients (n = 24) was breast pain. Thirty-two patients were found to have 44 ruptured implants, the majority of whom were found to have either contracture (n = 7) or negative findings (n = 7) on physician examination. The likelihood of rupture increased with number of years in place. When a patient presents for a possible implant rupture, the initial concern is to rule out malignancy, but because clinical and radiologic findings are often convoluted and complicated, a decision tree is helpful.

Overview of breast cancer staging and surgical treatment options.

Following diagnosis of breast cancer, patients undergo assessment for local and systemic treatment. Establishing a relationship and communication with the patient is critical to this assessment, as are history-taking, clinical breast examination, review of imaging studies, and interactive discussion with the patient of treatment options and possible breast reconstruction. Some type of surgical therapy is indicated in virtually all women with breast cancer, generally as the first part of a multicomponent treatment plan. The main goal of surgical therapy is to remove the cancer and accurately define the stage of disease. Surgical options broadly consist of breast conservation therapy, generally followed by radiation therapy, or mastectomy. The surgical procedure also includes assessment of regional lymph nodes for metastasis, either by axillary lymph node dissection or by the less-invasive sentinel lymph node biopsy, for the purpose of cancer staging and guiding adjuvant therapy.

In vivo margin assessment during partial mastectomy breast surgery using raman spectroscopy.

We present the first demonstration of in vivo collection of Raman spectra of breast tissue. Raman spectroscopy, which analyzes molecular vibrations, is a promising new technique for the diagnosis of breast cancer. We have collected 31 Raman spectra from nine patients undergoing partial mastectomy procedures to show the feasibility of in vivo Raman spectroscopy for intraoperative margin assessment. The data was fit with an established model, resulting in spectral-based tissue characterization in only 1 second. Application of our previously developed diagnostic algorithm resulted in perfect sensitivity and specificity for distinguishing cancerous from normal and benign tissues in our small data set. Significantly, we have detected a grossly invisible cancer that, upon pathologic review, required the patient to undergo a second surgical procedure. Had Raman spectroscopy been used in a real-time fashion to guide tissue excision during the procedure, the additional reexcision surgery might have been avoided. These preliminary findings suggest that Raman spectroscopy has the potential to lessen the need for reexcision surgeries resulting from positive margins and thereby reduce the recurrence rate of breast cancer following partial mastectomy surgeries.

Fluorescence in situ hybridization (FISH) as primary methodology for the assessment of HER2 Status in adenocarcinoma of the breast: a single institution experience.

The demand for both reflexed and primary fluorescence in-situ hybridization (FISH) testing in the clinical setting is increasing. Relevant literature has reported the incidence of HER2 overexpression in 20% to 30% of cases, but some reports suggest that HER2 gene amplification rates are substantially lower. Published data, however, on primary FISH assessment from a single institution is limited, especially information about the frequency of the anomalous genotypes defined by FISH. We report our experience with primary FISH testing in 742 consecutive cases of breast cancer, in the calendar year 2006. Eighty percent (595/742) of the breast cancer cases were not amplified for HER2 (HER2/CEP17=0.8-1.9), whereas 19% (142/742) of cases were HER2 amplified (HER2/CEP17>or=2.0). Among the HER2-amplified cases, 3% (19/742) were low-level amplified (HER2/CEP17 ratio=2.0-2.5). Genotypic heterogeneity, defined as >5% but <50% of the tumor cells demonstrating HER2 gene amplification, was observed in 5% (40/7242) of the cases. HER2 monoallelic deletion (HER2/CEP1780% of tumor cells) was observed in 2% (13/742). Polysomy, if defined as CEP17 spot count 3.0 or more in at least 80% of tumor cells, was observed in 3% (20/742) of the cases. These data may be helpful as benchmarks for other institutions initiating primary FISH analysis for HER2 genotyping.

Loss of breast cancer metastasis suppressor 1 protein expression predicts reduced disease-free survival in subsets of breast cancer patients.

PURPOSE: This study aims to determine the effect of loss of breast cancer metastasis suppressor 1 (BRMS1) protein expression on disease-free survival in breast cancer patients stratified by estrogen receptor (ER), progesterone receptor (PR), or HER2 status, and to determine whether loss of BRMS1 protein expression correlated with genomic copy number changes. EXPERIMENTAL DESIGN: A tissue microarray immunohistochemical analysis was done on tumors of 238 newly diagnosed breast cancer patients who underwent surgery at the Cleveland Clinic between January 1, 1995 and December 31, 1996, and a comparison was made with 5-year clinical follow-up data. Genomic copy number changes were determined by array-based comparative genomic hybridization in 47 breast cancer cases from this population and compared with BRMS1 staining. RESULTS: BRMS1 protein expression was lost in nearly 25% of cases. Patients with tumors that were PR negative (P=0.006) or HER2 positive (P=0.039) and <50 years old at diagnosis (P=0.02) were more likely to be BRMS1 negative. No overall correlation between BRMS1 staining and disease-free survival was observed. A significant correlation, however, was seen between loss of BRMS1 protein expression and reduced disease-free survival when stratified by either loss of ER (P=0.008) or PR (P=0.029) or HER2 overexpression (P=0.026). Overall, there was poor correlation between BRMS1 protein staining and copy number status. CONCLUSIONS: These data suggest a mechanistic relationship between BRMS1 expression, hormone receptor status, and HER2 growth factor. BRMS1 staining could potentially be used in patient stratification in conjunction with other prognostic markers. Further, mechanisms other than genomic deletion account for loss of BRMS1 gene expression in breast tumors.

Breast cancers with brain metastases are more likely to be estrogen receptor negative, express the basal cytokeratin CK5/6, and overexpress HER2 or EGFR.

Brain metastases (BM) from breast cancer are associated with significant morbidity and mortality. In the current study, we have examined a cohort of breast cancer patients who went on to develop BM for clinical-pathologic features and predictive markers that identify this high-risk subgroup of patients at the time of diagnosis. The primary tumors from 55 patients who developed BM were used to construct a tissue microarray. The clinical and pathologic features were recorded and the tissue microarray was stained for estrogen receptor, human epidermal growth factor receptor 2, cytokeratin 5/6, and epidermal growth factor receptor by immunohistochemistry. This cohort of patients was compared against a group of 254 patients who remain free of metastases (67 mo mean follow-up), and another cohort of 40 patients who developed mixed visceral and bone metastatic disease without brain recurrence over a similar period of time. Breast cancer patients who went on to develop BM were more likely to be <50 years old (P<0.001), and the primary tumors were more likely to be estrogen receptor negative (P<0.001) and high grade (P=0.002). The primary tumors were also more likely to express cytokeratin 5/6 (P<0.001) and epidermal growth factor receptor (P=0.001), and to overexpress human epidermal growth factor receptor 2 (P=0.001). The data presented above suggest a profile for breast cancer patients at increased risk for developing BM. Predictive factors to help identify patients with metastatic breast cancer who are at an increased risk for developing central nervous system recurrence might allow for screening of this population for early detection and treatment or for the development of targeted strategies for prevention.

HER-2 amplification in tubular carcinoma of the breast.

The prognostic and therapeutic implications of HER-2 gene amplification and estrogen and progesterone receptor status in breast cancer are well described. To address the relative paucity of information concerning HER-2 amplification for tubular carcinomas, we assessed the frequency of gene amplification in 55 tubular carcinomas of the breast from 54 patients, 5 of which had axillary node metastases. The HER-2 gene copy number was assessed by fluorescence in situ hybridization for the majority of tumors analyzed, whereas estrogen and progesterone receptor status was achieved by immunohistochemical analysis. HER-2 gene amplification was not observed in any of the tumors examined, and most were estrogen receptor-positive. This HER-2 gene amplification frequency was significantly lower than the frequency of gene amplification previously reported for all invasive ductal carcinoma of no special type (P < .01). HER-2 gene amplification likely occurs infrequently, or not at all, in tubular carcinomas of the breast, whereas most express estrogen receptors.

A data model to predict HER2 status in breast cancer based on the clinical and pathologic profiles of a large patient population at a single institution.

Recently published clinical trial data have produced compelling evidence for increased survival when Herceptin is administered to patients whose tumors are HER2 amplified. Therefore, the accuracy of HER2 status is essential to determine which patients should or should not receive Herceptin. Although HER2 results obtained by FISH and IHC are often in agreement, there is a persistent group of cases in which results are discordant, particularly among tumors with intermediate results. A multivariable analysis was undertaken to determine relative significance of various clinical and pathologic findings for patients diagnosed with infiltrating ductal carcinoma, and a data model was produced that predicts which patients are most likely to have HER2 amplified tumors. Correlates of HER2 amplification were higher Scarff-Bloom-Richardson grade, younger age at diagnosis, and a comedo ductal carcinoma in situ component.

The clinical applications of mammary ductoscopy.

BACKGROUND: Mammary ductoscopy (MD) is a newly developed endoscopic technique that allows direct visualization and biopsy examination of the mammary ductal epithelium where most cancers originate. The procedure can be performed under local anesthesia in the office setting. This article reviews the rationale, current clinical applications, and limitations of MD. METHODS: A literature search was performed using Pubmed for indexed articles published over the past 30 years using the key words "mammary ductoscopy," "breast ductoscopy," "ductal lavage," and "nipple aspiration." The most important articles were analyzed and discussed. RESULTS: MD is a useful diagnostic adjunct in patients with pathologic nipple discharge. Furthermore, it can reduce the number and extent of duct excision surgeries for pathologic nipple discharge. There is a clear need to design prospective clinical trials that evaluate the potential role of MD in breast cancer screening, guiding risk-reducing strategies, and as an adjunct to breast-conservation surgery. CONCLUSIONS: MD is useful in the management of PND, but its potential role in the early detection or management of breast cancer requires further investigation.

Identification of breast cancer in patients with pathologic nipple discharge: does ductoscopy predict malignancy?

OBJECTIVE: The purpose of the current study was to review characteristics of patients with nipple discharge who underwent ductoscopy-assisted excisional biopsy who had a final diagnosis of carcinoma. METHODS: A retrospective review was performed of patients presenting with pathologic nipple discharge (PND) who underwent ductoscopy-assisted excisional biopsy and had a final diagnosis of carcinoma. RESULTS: A total of 14 (7%) of 188 patients who underwent ductoscopy-assisted excision had a final pathology of ductal carcinoma-in-situ (DCIS) (12/14, 86%) or invasive breast cancer with DCIS (2/14, 14%). Duct wall irregularities or intraluminal growths were visualized during ductoscopy in 8 of the 14 (57%) breast cancer patients. There were no visual abnormalities noted during ductoscopy that accurately predicted a final diagnosis of malignancy. CONCLUSIONS: Although occult malignancies can be identified in patients undergoing ductoscopy-assisted biopsy for PND, no clear morphologic changes visualized during ductoscopy definitively indicated the presence of malignancy.

Breast surgery: minimally invasive diagnosis and treatment.

The increasingly large proportion of elderly women in the United States population carries a disproportionate burden of breast cancer. The advent of minimally invasive surgical techniques applicable to breast disease has brought new opportunities to diagnose and treat breast cancer in the older population. This article reviews issues important to the evolving field of breast cancer management in older women: cancer risk and screening considerations, diagnosis and biopsy approaches, and surgical treatment options based on current studies and recommendations.

HER2 status in bilateral breast cancer.

BACKGROUND: The purpose of this study was to identify correlates of HER2 status for patients with bilateral breast cancer. METHODS: Data were collected prospectively in our institutional review board approved patient registry for all patients with asynchronous (ABBC) and synchronous (SBBC) bilateral infiltrating breast cancer whose HER2 assays were performed at our laboratory using FISH. Data were analyzed using the Wilcoxon rank sum and Chi-square test. RESULTS: Data were available for 98 tumors in 49 patients. Patients diagnosed with SBBC were more likely to be white (P = 0.023); to have bilateral HER2 non-amplified tumors (P = 0.022) and to be older at diagnosis (P = 0.025) compared to those with ABBC. Patients with one HER2 amplified tumor were likely to have at least one tumor be hormone receptor negative and to have ABBC. CONCLUSIONS: Only 16% of patients in this study had one tumor that was HER2 amplified; no patient had bilateral HER2 amplified tumors.