Laura S. Dominici

Contralateral prophylactic mastectomy in women with breast cancer: trends, predictors, and areas for future research.

Recent studies have revealed increasing rates of contralateral prophylactic mastectomy (CPM) among women with unilateral early stage breast cancer. This trend has raised concerns, given the lack of evidence for a survival benefit from CPM and the relatively low risk of contralateral breast cancer for most women in this setting. In this article, we review available data regarding the value of CPM, predictors, and outcomes related to CPM, and areas for future research and potential intervention.

Implications of constructed biologic subtype and its relationship to locoregional recurrence following mastectomy

IntroductionWe examined the prognostic value of biologic subtype on locoregional recurrence (LRR) after mastectomy in a cohort of low risk women who did not receive adjuvant radiation therapy.MethodsA total of 819 patients with invasive breast cancer underwent mastectomy from January 2000 through December 2005. No patient received preoperative chemotherapy. Estrogen receptor (ER) receptor, progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) status were used to construct the following 4 subtypes: i) ER+ or PR+ and HER2- (HR+/HER2-), ii) ER+ or PR+ and HER2+ (HR+/HER2+), iii) ER- and PR- and HER2+ (HR-/HER2+)and iv) ER- and PR- and HER2- (HR-/HER2-). LRR-free survival was estimated by the Kaplan-Meier method. Cox proportional hazard models were used to evaluate the association between time-to-event outcomes and patient prognostic factors.ResultsAt a median follow-up of 58 months, five-year cumulative incidence of LRR for the entire cohort was 2.5%. Subtype specific LRR rates were 1% for HR+/HER2-, 6.5% in HR+/HER2+, 2% for HR-/HER2+ and 10.9% for HR-/HER2- (P < 0.01). In HER-2+ patients (irrespective of ER/PR status), trastuzumab therapy was not associated with LRR-free survival. On multivariate analysis, one to three positive lymph nodes (HR 4.75 (confidence interval (CI) 1.75 to 12.88, P < 0.01), ≥ 4 positive lymph nodes (HR23.4 (CI 4.64 to 117.94, P < 0.01), HR+/HER2+ (HR 4.26 (CI 1.05 to 17.33), P = 0.04), and HR-/HER2- phenotype (HR 13.87 (CI 4.96 to 38.80), P < 0.01) were associated with shorter LRR-free survival whereas age > 50 at diagnosis (HR 0.31 (CI 0.12 to 0.80), P = 0.02) was associated with improved LRR-free survival. Among the HR-/HER2- subtypes, five-year LRR incidence was 23.4% in patients with positive lymph nodes compared to 7.8% for lymph node negative patients (P = 0.01), although this association did not reach significance when the analysis was limited to HR-/HER2- women with only one to three positive lymph nodes (15.6% versus 7.8%, P = 0.11).ConclusionsConstructed subtype is a prognostic factor for LRR after mastectomy among low risk women not receiving adjuvant radiation therapy, although rates of LRR remain low across subtypes. Patients with node positive, HR-/HER2- type tumors were more likely to experience LRR following mastectomy alone. Prospective studies to further investigate the potential benefit of adjuvant radiation therapy in these women are warranted.

Wound complications from surgery in pregnancy-associated breast cancer (PABC)

BACKGROUND there are concerns that physiologic changes of the peripartum breast may result in complications in breast conservation therapy. We present the complications of breast conservation surgeries and mastectomies performed for pregnancy-associated breast cancer (PABC). MATERIALS AND METHODS from April 1989 through April 2008, sixty-seven breast cancer patients underwent surgical management for PABC, defined as surgery during pregnancy or within one year postpartum. Records of women who had surgery were examined for post-operative wound complications of milk fistula, cellulitis, abscess, or hematoma. RESULTS Forty-seven patients underwent mastectomy. Twenty were treated with conservative breast surgery. There were six complications, all treated in the outpatient setting. There were no documented milk fistulae. CONCLUSIONS in our series, we had few postoperative complications and no milk fistulae for those patients undergoing surgery for PABC. When compared to those who had mastectomy for PABC, women who underwent breast conserving therapy did not appear to have increased frequency of surgical complications.

State Variation in the Receipt of a Contralateral Prophylactic Mastectomy Among Women Who Received a Diagnosis of Invasive Unilateral Early-Stage Breast Cancer in the United States, 2004-2012

Importance The use of contralateral prophylactic mastectomies (CPMs) among patients with invasive unilateral breast cancer has increased substantially during the past decade in the United States despite the lack of evidence for survival benefit. However, whether this trend varies by state or whether it is correlated with changes in proportions of reconstructive surgery among these patients is unclear. Objective To determine state variation in the temporal trend and in the proportion of CPMs among women with early-stage unilateral breast cancer treated with surgery. Design, Setting, and Participants A retrospective cohort study of 1.2 million women 20 years of age or older diagnosed with invasive unilateral early-stage breast cancer and treated with surgery from January 1, 2004, through December 31, 2012, in 45 states and the District of Columbia as compiled by the North American Association of Central Cancer Registries. Data analysis was performed from August 1, 2015, to August 31, 2016. Exposure Contralateral prophylactic mastectomy. Main Outcomes and Measures Temporal changes in the proportion of CPMs among women with early-stage unilateral breast cancer treated with surgery by age and state, overall and in relation to changes in the proportions of those who underwent reconstructive surgery. Results Among the 1 224 947 women with early-stage breast cancer treated with surgery, the proportion who underwent a CPM nationally increased between 2004 and 2012 from 3.6% (4013 of 113 001) to 10.4% (12 890 of 124 231) for those 45 years or older and from 10.5% (1879 of 17 862) to 33.3% (5237 of 15 745) for those aged 20 to 44 years. The increase was evident in all states, although the magnitude of the increase varied substantially across states. For example, among women 20 to 44 years of age, the proportion who underwent a CPM from 2004-2006 to 2010-2012 increased from 14.9% (317 of 2121) to 24.8% (436 of 1755) (prevalence ratio [PR], 1.66; 95% CI, 1.46-1.89) in New Jersey compared with an increase from 9.8% (162 of 1657) to 32.2% (495 of 1538) (PR, 3.29; 95% CI, 2.80-3.88) in Virginia. In this age group, CPM proportions for the period from 2010 to 2012 were over 42% in the contiguous states of Nebraska, Missouri, Colorado, Iowa, and South Dakota. From 2004 to 2012, the proportion of reconstructive surgical procedures among women aged 20 to 44 years who were diagnosed with early-stage breast cancer and received a CPM increased in many states; however, it did not correlate with the proportion of women who received a CPM. Conclusions and Relevance The increase in the proportion of CPMs among women with early-stage unilateral breast cancer treated with surgery varied substantially across states. Notably, in 5 contiguous Midwest states, nearly half of young women with invasive early-stage breast cancer underwent a CPM from 2010 to 2012. Future studies should examine the reasons for the geographic variation and increasing trend in the use of CPMs.

Current surgical approach to Paget's disease

BACKGROUND Pagets disease constitutes between 1% and 3% of all breast malignancies, which makes defining standard surgical therapy difficult. We sought to identify preoperative factors that would select patients for successful breast conservation. METHODS Fifty-one patients with Pagets disease underwent surgical therapy between October 1998 and January 2010. Clinical presentation of Pagets disease, preoperative imaging, pathologic tumor characteristics, as well as surgical, radiation, and adjuvant therapies were reviewed. RESULTS Thirty-seven percent underwent breast conservation whereas 63% underwent mastectomy. Twelve patients presented with a palpable mass, and all were treated with mastectomy. Twenty-two patients underwent a mammogram, identifying extensive abnormality requiring mastectomy. Magnetic resonance imaging added to surgical planning in 52% of patients who participated in the study. None of our patients had a local/regional recurrence at 29 months of follow-up evaluation. CONCLUSIONS Pagets disease of the breast can be treated with breast conservation in a properly selected subset of patients. Successful breast conservation was achieved in patients without a palpable finding, a benign mammogram, and a normal magnetic resonance imaging scan.

Paget disease of the breast with invasion from nipple skin into the dermis: an unusual type of skin invasion not associated with an adverse outcome.

CONTEXT Paget disease is an uncommon skin manifestation of breast cancer, associated with either invasive carcinoma or ductal carcinoma in situ in the underlying breast. In very rare cases, tumor cells within the epidermis invade through the basement membrane of the skin into the dermis. OBJECTIVES To identify a series of cases of Paget disease with direct dermal invasion and to investigate the clinicopathologic features and outcome. DESIGN Cases were identified during a 6-year period from the files of 2 hospitals. The clinical histories, imaging studies, and pathology reports were reviewed. RESULTS Seven patients were identified, 5 with microinvasion (<0.1 cm) and 2 with 0.2- or 0.3-cm invasive carcinomas in the dermis. No lymphovascular invasion was seen. Sentinel nodes were negative in 3 patients who underwent biopsy. Five patients were treated with breast conservation with radiation. Three patients were at high risk for breast cancer because of prior breast cancer, Li-Fraumeni syndrome, or radiation for Hodgkin disease. The latter 2 patients underwent bilateral mastectomies. Three patients received hormonal therapy and 1 oophorectomy. No patient received chemotherapy. At follow-ups ranging from 4 to 66 months (median, 20 months), there have been no recurrences. CONCLUSIONS Patients with direct dermal invasion from Paget disease had a favorable outcome during the available follow-up period. This type of dermal involvement must be distinguished from locally advanced invasive carcinomas with skin invasion classified as T4b in the American Joint Cancer Commission staging system, as cancers with other types of skin invasion are associated with a poor prognosis.

Young women with breast cancer in the United States and South Korea: comparison of demographics, pathology and management.

BACKGROUND Breast cancer diagnosed in young women may be more aggressive, with higher rates of local and distant recurrence compared to the disease in older women. Epidemiologic evidence suggests that Korean women have a lower incidence of breast cancer than women in the United States, but that they present at a younger age than their American counterparts. We sought to compare risk factors and management of young women with breast cancer in Boston, Massachusetts (US) with those in Seoul, South Korea (KR). MATERIALS AND METHODS A retrospective review was performed of consecutive patients less than 35 years old with a diagnosis of breast cancer at academic cancer centers in the US and KR from 2000-2005. Patient data were obtained by chart review. Demographic, tumor and treatment characteristics were compared utilizing Pearsons chi- square or Wilcoxon rank-sum tests where appropriate. All differences were assessed as significant at the 0.05 level. RESULTS 205 patients from the US and 309 from KR were analyzed. Patients in US were more likely to have hormone receptor positive breast cancer, while patients in KR had a higher rate of triple negative lesions. Patients in US had a higher mean body mass index and more often reported use of birth control pills, while those in the KR were less likely to have a sentinel node procedure performed or to receive post mastectomy radiation. CONCLUSIONS Patients under 35 diagnosed with breast cancer in the US and KR differ with respect to demographics, tumor characteristics and management. Although rates of breast conservation and mastectomy were similar, US patients were more likely to receive post mastectomy radiation. The lower use of sentinel node biopsy is explained by the later adoption of the technique in KR. Further evaluation is necessary to evaluate recurrence rates and survival in the setting of differing disease subtypes in these patients.

Large Needle Core Biopsy of Atypical Ductal Hyperplasia: Results of Surgical Excision

To the Editor: Atypical ductal hyperplasia (ADH) is present in 5–15% of breast biopsies performed for calcifications and is found less frequently in biopsies performed for mammographic densities or masses (1,2). For women diagnosed with ADH after biopsy, the risk of developing breast cancer is roughly four times that of the general population (3). ADH diagnosed on core needle biopsy has traditionally resulted in recommendation for surgical excision to rule out adjacent or associated non-invasive or invasive breast cancer. After surgical excision, rates of finding disease more severe than ADH (the rate of upgrade) depends on the gauge of the core needle biopsy, number of cores taken, and size and type of mammographic abnormality. More recent data using automated breast biopsy devices show a lower rate of occult carcinoma among patients with a diagnosis of ADH on core biopsy, presumably resulting from more extensive tissue sampling and the greater likelihood of complete removal of the radiological lesions (2,4). The rate of upgrade to carcinoma with the 11-gauge (G) vacuum-assisted biopsy devices is reported between 15% and 19% (4,5). We sought to review our recent experience with the surgical excision of ADH identified after needle core biopsy to determine if the routine use of an 11-G core needle and vacuum-assist technique results in lower rate of upgrade, making it possible for selected patients to avoid surgical excision. We reviewed consecutive cases (2003–2007) of image-guided core biopsy performed on mammographic abnormalities, which revealed ADH. Our institutional review board approved this retrospective study. In all patients, core biopsy revealed ADH after formal pathology review by the breast pathology service at our institution. We reviewed 166 cases of ADH that had both core biopsy and surgical excision performed at our institution. Standard hematoxylin– eosin slides were prepared and reviewed by a subspecialty breast pathologist. Biopsies were performed by experienced radiologists using stereotactic guidance on a dedicated stereotactic core biopsy unit (Lorad; Hologic, Danbury, CT). The biopsies were performed using a vacuum-assisted biopsy device (Mammotome; Ethicon Endo-Surgery, Cincinnati, OH). The majority of patients, 93% (155), underwent core biopsy with an 11 G or larger device. The mean number of cores taken was eight. All clusters of calcifications were sampled using radiographic images, and imaging to confirm sampling of targeted calcifications was obtained in all cases. A 2 · 2 mm radiopaque localizing clip (MicroMark; Ethicon Endo-Surgery) was placed at the biopsy site to provide an accurate target for wire localization should excisional biopsy become necessary. Surgical excisional biopsies were performed by dedicated breast surgeons. Cases with an initial histopathologic diagnosis of ADH at image-guided core needle biopsy that subsequently yielded ductal carcinoma

Immediate breast reconstruction following mastectomy in pregnant women with breast cancer

Surgical management of breast cancer in pregnancy (BCP) requires balancing benefits of therapy with potential risks to the developing fetus. Minimal data describe outcomes after mastectomy with immediate breast reconstruction (IR) in pregnant patients.

Breast Cancer Axillary Staging: Much Ado About Micrometastatic Disease

The primary goals of diagnostic cancer staging are to provide prognostic information and to inform treatment recommendations. The use of uniform staging definitions also allows clinicians and researchers to communicate in a common language and to place cancer outcomes, whether in the context of clinical trials, observational studies, or population-based cohorts, into their proper context. The most commonly used staging system in breast cancer relies almost exclusively on anatomic features and is defined as “tumor node metastasis” (TNM). The American Joint Committee on Cancer (AJCC) and the Union for International Cancer Control (UICC) developed TNM staging in 1978 and have periodically refined it since that time, with the most recent seventh edition completed in 2010. At least two features of AJCC staging are worth noting: first, the definition (in 2010) of T1N1mi disease as stage IB, and second, the absence of consideration of tumor biologic subtype despite a growing awareness of the seminal importance of subtype on breast cancer outcomes. In patients with breast cancer, staging of the regional lymph nodes has traditionally been an integral part of management, and nodal status is considered a significant factor in prognostication and selection of multimodality therapy. After years of surgically clearing the axilla of nodal tissue, contemporary surgical management favors sentinel lymph node dissection (SLND). This procedure continues to provide the necessary diagnostic and prognostic information, while limiting morbidity and improving quality of life. As SLND has gained acceptance, efforts have been made to evaluate and report extent of disease within the axilla with greater precision. Extensive pathologic analysis has resulted in a complex system of nodal classification, including isolated tumor cells and micrometastases, which has generated significant debate as to the clinical relevance of small tumor deposits that likely would not have been identified in many cases in the era of routine axillary dissection. Put simply, the debate has centered on whether the detection of small-volume axillary disease identifies patients at higher risk of recurrence and whether these individuals warrant additional measures to reduce that risk. In this issue of the Journal of Clinical Oncology, Mittendorf et al present an analysis that challenges the relevance of the current stage I classification. The authors analyzed more than 8,000 patients with breast cancer from two prospective cohorts containing approximately 5,580 patients with stage I disease (5,000 stage IA [T1N0] and 580 stage IB [T0-1N1mi]), with 6.5 to 9 years median follow-up. One cohort was derived from a series at MD Anderson Cancer Center (MDACC) of clinically node-negative patients undergoing SLND; the other came from the American College of Surgeons Oncology Group ACOSOGZ0010 trial (Prognostic Study of Sentinel Lymph Node and Bone Marrow Metastases in Women With Stage I or Stage IIA Breast Cancer) and included patients with T1-2N0 disease. In both studies, the SLN was evaluated by hematoxylin and eosin (HE) staining; at MDACC, all nodes were also analyzed by immunohistochemistry (IHC), and providers were aware of results. In the ACOSOG-Z0010 trial, however, IHC was used only if the HE analysis was negative, with providers blinded to IHC results. Adjuvant trastuzumab was not administered as part of therapy at the time of the studies. Analysis of each cohort demonstrated no significant difference in survival end points, including recurrence-free and overall survival, between stage IA and IB disease. Their data align with other recent analyses from ACOSOG-Z0010 and National Surgical Adjuvant Breast and Bowel Project NSABP B-32 (Surgery to Remove Sentinel Lymph Nodes With or Without Removing Lymph Nodes in the Armpit in Treating Women With Breast Cancer) regarding the minimal prognostic utility of identifying occult small-volume SLN disease. As expected, generally inferior survival was observed in the comparison of stage IIA with the stage I categories. In a secondary analysis, biologic features, including estrogen receptor status and locally determined grade, were able to stratify survival outcomes in stage I patients. Therefore, on the basis of these findings, Mittendorf et al raise the question: if cancer staging is designed to stratify patients by prognosis, how can we support a category which does not refine our ability to present risk to patients? In addition, although traditional staging is defined by anatomy, is it possible to incorporate aspects of tumor biology? Multiple recent observations have recognized the importance of biologic factors in prognostication for small, node-negative tumors. In general, it is acknowledged that patients presenting with stage I breast cancer generally carry an excellent prognosis, although survival outcomes may vary by biologic subtype. Several observational studies have confirmed increased risks for small human epidermal growth factor receptor 2 (HER2) –positive cancers compared with same stage hormone receptor–positive and/or HER2-negative tumors. Given the recognition of increased risk, successful application of HER2-directed therapy for small HER2-positive cancers has translated into highly favorable outcomes and has become a standard of care for many stage 1 patients. Likely related to the recognition JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 33 NUMBER 10 APRIL 1 2015