Theresa Schwartz

Tumor-Infiltrating γδ T Lymphocytes Predict Clinical Outcome in Human Breast Cancer

Understanding and dissecting the role of different subsets of regulatory tumor-infiltrating lymphocytes (TILs) in the immunopathogenesis of individual cancer is a challenge for anti-tumor immunotherapy. High levels of γδ regulatory T cells have been discovered in breast TILs. However, the clinical relevance of these intratumoral γδ T cells is unknown. In this study, γδ T cell populations were analyzed by performing immunohistochemical staining in primary breast cancer tissues from patients with different stages of cancer progression. Retrospective multivariate analyses of the correlations between γδ T cell levels and other prognostic factors and clinical outcomes were completed. We found that γδ T cell infiltration and accumulation in breast tumor sites was a general feature in breast cancer patients. Intratumoral γδ T cell numbers were positively correlated with advanced tumor stages, HER2 expression status, and high lymph node metastasis but inversely correlated with relapse-free survival and overall survival of breast cancer patients. Multivariate and univariate analyses of tumor-infiltrating γδ T cells and other prognostic factors further suggested that intratumoral γδ T cells represented the most significant independent prognostic factor for assessing severity of breast cancer compared with the other known factors. Intratumoral γδ T cells were positively correlated with FOXP3+ cells and CD4+ T cells but negatively correlated with CD8+ T cells in breast cancer tissues. These findings suggest that intratumoral γδ T cells may serve as a valuable and independent prognostic biomarker, as well as a potential therapeutic target for human breast cancer.

Metaplastic breast cancer: histologic characteristics, prognostic factors and systemic treatment strategies.

Metaplastic breast cancer (MBC) is a rare subtype of invasive breast cancer that tends to have an aggressive clinical presentation as well as a variety of distinct histologic designations. Few systemic treatment options are available for MBC, as it has consistently shown a suboptimal response to standard chemotherapy regimens. These characteristics result in a worse overall prognosis for patients with MBC compared to those with standard invasive breast cancer. Due to its rarity, data focusing on MBC is limited. This review will discuss the clinical presentation, breast imaging findings, histologic and molecular characteristics of MBC as well as potential future research directions.

Should Re-excision Lumpectomy Rates Be a Quality Measure in Breast-Conserving Surgery?

In response to recognition of variation in the quality of national healthcare, physicians and their professional societies have emphasized the need for quality measurement and improvement. Multiple organizations have now developed breast-specific quality measures (QM) to aid quality improvement (QI). Many of these QM have been incorporated into national quality initiatives that provide peer performance comparison and some level of transparency. In addition, during the last decade, the American Society of Breast Surgeons (ASBS), the National Accreditation Program for Breast Centers (NAPBC), and the National Consortium of Breast Centers (NCBC) have defined and endorsed multiple breast-specific quality measures. A QM is an attempt to quantify quality in a domain of care. The most common historical domains of care are ‘‘structure of care,’’ ‘‘process of care,’’ and outcomes. Recently, ‘‘patient centeredness (experience)’’ and ‘‘affordability’’ have been emphasized as other important domains of quality care. In order to protect against indiscriminate use of metrics that may not be good measures, the federal government has defined QM as ‘‘measures used to assess the performance of individual clinicians, clinical delivery teams, delivery organizations, or health insurance plans in the provision of care to their patients or enrollees, which are supported by evidence demonstrating that they indicate better or worse care.’’ The last phrase is a key part of the definition, indicating that in order for a proposed measure to meet this definition, there must be supporting evidence that the measure can gauge differences in care. There are many aspects to the quality of breast-conserving surgery (BCS). These include typical operative outcomes, such as surgical site infection, myocardial infarction, and thromboembolic events. Fortunately, these complications occur so infrequently in BCS that they have limited potential for improvement. Identifying those areas of BCS that could benefit from quality measurement has recently drawn national attention. Re-excision lumpectomy rates (RELR) after BCS for breast cancer has been discussed as a potential quality measure by the ASBS. However, its use as a quality measure is controversial and is greatly debated. There are divergent opinions amongst breast surgeons regarding whether to call RELR a QM or whether to use RELR for QI. The primary argument for its use as a QM is strong evidence of significant variability of RELR, ranging from 0 to 70 %. On the other hand, the use of RELR as a QM may reduce secondary operations at the cost of unintended harmful changes to other measures of BCS quality. It has also been argued that there is no direct link between RELR and ‘‘quality.’’ This argument is valid if the only quality outcome measured is ipsilateral breast tumor recurrence (IBTR). IBTR has never been demonstrated to differ between patients who require single versus multiple operations to achieve a negative margin. In a broader view, there may be linkage between RELR and quality. Patient experience and affordability are domains of quality endorsed by the National Quality Forum and others. Both would be expected to improve by lowering the RELR. Central to the issue of re-excision after lumpectomy is the topic of surgical margins. Surgeons perform re-excision lumpectomies in order to obtain adequate margins, as margin status is associated with IBTR. However, what Society of Surgical Oncology 2013

Screening breast magnetic resonance imaging in women with atypia or lobular carcinoma in situ

BACKGROUND Atypical lesions and lobular carcinoma in situ (LCIS) are associated with an increased risk of breast malignancy. The utility of breast magnetic resonance imaging (MRI) screening in this cohort of women after excision of a high-risk lesion has not been previously established. The objective of this study was to investigate outcomes of breast MRI surveillance in this subgroup of high-risk patients. MATERIALS AND METHODS We performed a retrospective review of women who required excision of an atypical lesion or LCIS who underwent at least one screening breast MRI from April 2005-December 2011. We collected information on demographics, number of second-look imaging studies recommended, number of biopsies performed and pathologic outcomes. RESULTS A total of 179 patients met the inclusion criteria, including 131 (73%) with atypical lesions and 48 (27%) with LCIS. Second-look imaging was recommended for 31 of 131 (23.7%) patients with atypical lesions and 8 of 48 (16.7%) with LCIS. Ten biopsies were performed in the atypical cohort (7.6%) with two revealing a malignancy (Positive Predictive Value [PPV] of 20%). In the LCIS cohort, five biopsies were performed (10.4%) with one revealing a malignancy (PPV of 20%). CONCLUSIONS The benefit of breast MRI surveillance in patients after excision of atypical lesions or LCIS has not been clearly delineated previously. Our data demonstrate that the use of screening breast MRI in this cohort results in additional work-up in one-fifth of patients, but a PPV of only 20%. Large, prospective studies would be needed to determine whether breast cancer outcomes differ between patients undergoing conventional breast screening and those undergoing conventional breast screening plus breast MRI surveillance.

Accessory spleen masquerading as a pancreatic neoplasm

A patient with a pancreatic mass noted on a computed tomography scan was suspected of having a nonfunctioning pancreatic neuroendocrine neoplasm. The eventual diagnosis of intrapancreatic accessory spleen was made by noninvasive means, thus avoiding unnecessary surgery.

The effect of marital status on breast cancer-related outcomes in women under 65: A SEER database analysis

BACKGROUND Marital status is strongly associated with improved health and longevity. Being married has been shown to be positively associated with survival in patients with multiple different types of malignancy; however, little is known about the relationship between marital status and breast cancer in younger women. The purpose of this study is to investigate the effect of marital status on diagnosis, and survival of women under the age of 65 with breast cancer. METHODS The SEER 18 regions database was used to identify women between the ages of 25-64 diagnosed with invasive breast cancer in the years 2004-2009. Logistic regression was used to predict later stage diagnosis by marital status and Cox proportional hazards models were used to compare breast cancer-related and all-cause survival by marital status classification. Models were stratified by AJCC stage. RESULTS After adjusting for age, race, and ER status, unmarried women were 1.18 times more likely to be diagnosed at a later stage than married women (95% CI 1.15, 1.20). In adjusted analysis unmarried women were more likely to die of breast cancer and more likely to die of all causes than married women across all AJCC stages. CONCLUSIONS Younger unmarried women with breast cancer may benefit from additional counseling, psychosocial support and case management at the time of diagnosis to ensure their overall outcomes are optimized.

Axillary Ultrasound Before Neoadjuvant Chemotherapy for Breast Cancer: Don’t Discount the Benefits Yet!

Axillary lymph node status remains a top prognostic indicator for patients with breast cancer. It has been well established that the extent of nodal involvement plays a key role in the risk for both local recurrence and overall survival, and nodal staging has a tremendous impact on systemic therapy and radiotherapy treatment recommendations. During the last 25 years, significant changes in our nodal assessment techniques have occurred, with a trend toward less invasive and less extensive dissections. After NSABP B-32, sentinel lymph node biopsy (SLNB) alone became the standard of care for nodal staging of clinically node-negative (cN0) patients. Then, ACOSOG Z0011 illustrated the safety of SLNB alone in conjunction with adjuvant whole-breast radiation for women with T1 or T2 tumors undergoing lumpectomy with two or fewer positive sentinel lymph nodes (SLN), thereby avoiding axillary lymph node dissection (ALND) for 84% of SLNB-positive patients. However, there continues to be a marked interest in identifying even less invasive, yet oncologically safe, strategies to establish nodal status. The use of axillary ultrasound (AUS) was initially described in 1989 and its use has expanded significantly during the last 25 years. The potential benefit of AUS is the ability to triage patients with nodal metastases for upfront ALND, thus avoiding the time and cost of a staged SLNB/ ALND. However, this strategy potentially results in unnecessary ALND for women who would otherwise meet the Z0011 criteria. The role of AUS staging is especially controversial in the setting of patients undergoing neoadjuvant chemotherapy (NAC). In this study by Barrio et al., the ability of pre-NAC AUS to predict nodal metastases after NAC was investigated with 402 cN0 patients receiving NAC between 2008 and 2016. Clinical nodal staging was performed by physical examination and collected by chart review. Of the 162 AUS procedures performed, 131 (81%) showed abnormal lymph nodes. Pathologic staging of these lymph nodes was performed via SLNB before NAC, SLNB alone, SLNB then ALND, or ALND alone. The incidence of positive lymph nodes after NAC was higher, yet not significantly different statistically (p = 0.1), for patients with an abnormal pre-NAC AUS. However, if abnormal axillary lymph nodes were identified on magnetic resonance imaging (MRI) or positron emission tomography (PET) and computed tomography (CT) before NAC, the patients had a significantly greater chance of having histologically positive lymph nodes (pN1) after NAC (p\ 0.001 for both). Differences in tumor biology were found between the patients with pN1 after NAC and the pathologically node-negative (pN0) patients. Nodal disease was more likely to be identified after NAC in the patients with nonductal histology [odds ratio (OR) 2.93; p = 0.003) and in those with estrogen receptor (ER) positivity (OR 3.94; p\ 0.001). The lower rate of response to NAC among patients with invasive lobular cancer and ER ? disease has been illustrated in previous studies. In the entire patient population of the current study, 20% of the patients with normal axillary lymph nodes identified on pre-NAC imaging were pN1 at the time of definitive surgery. Among 208 patients with abnormal lymph nodes identified by any imaging strategy, 65% were pN0 after NAC. The authors concluded that pre-NAC AUS did not predict the need for axillary Society of Surgical Oncology 2017

Sentinel Lymph Node Biopsy after Neoadjuvant Chemotherapy for Patients with Axillary Metastases: Can We Avoid the Unavoidable?

While initially implemented for patients with inoperable breast cancers, the use of neoadjuvant chemotherapy (NAC) was broadened to allow women to become candidates for breast conserving surgery. Clinical trials have shown no statistically significant differences in disease-free survival (DFS) and overall survival (OS) between patients who received NAC compared with those who received postoperative chemotherapy. Despite the evidence supporting the safety of a less extensive breast operation after a significant response to NAC, it has been a challenge to change the management of the axilla for definitive nodal staging in these patients. The safety and efficacy of sentinel lymph node biopsy (SLNB) for axillary staging was confirmed in NSABP B32, where this technique was shown to have equivalent OS, DFS, and regional control compared with axillary lymph node dissection (ALND) in clinically node-negative patients. This study, along with other large prospective trials, demonstrated low false negative rates (FNR) of\10 % with very low rates of axillary recurrence (1 %). The feasibility and accuracy of SLNB following NAC has been illustrated in multiple studies, most notably in NSABP B-27. In this study, the SLN identification rate was 85 % with a FNR of 8 % when dual tracer techniques were used. These findings, as well as those in other retrospective studies, have allowed surgeons to comfortably perform SLNB after NAC for patients with no evidence of axillary metastases prior to NAC. However, once metastatic disease was documented within the axilla prior to NAC, an ALND was the only form of nodal staging offered at the time of the definitive breast operation for the majority of patients. With the knowledge that NAC can decrease, if not completely diminish, tumor burden within the breast as well as the axilla, and that SLNB is feasible in this patient population, why have we been so reluctant to defer ALND in women who have been downstaged to clinically node negative following NAC? Three prospective studies have investigated the accuracy of SLNB after NAC in initially nodepositive patients and demonstrated variable FNRs; many were unacceptably high ([10 %) when the entire study population was included. However, when patients with C3 SLNs were analyzed, the FNRs decreased to\10 % in most cases. With the suggested benefit of analyzing C3 SLNs, the differences in methodologies as well as a median number of 2 SLNs examined in these prospective trials, critics have questioned the feasibility of performing an accurate SLNB after NAC. In this manuscript, Mamtani et al. attempted to answer this question with a single-center, prospective analysis investigating the frequency with which node-positive patients meet criteria for SLNB, with low FNR, following NAC. From 2013 to 2015, they identified 195 patients with stage II–III, node-positive disease at presentation who received NAC and completed surgery by November 2015. Those with clinical T4 or N2/N3 disease were excluded, leaving 155 evaluable patients. Of these, 132 (85 %) had a complete clinical response within the axilla by physical exam and were eligible for SLNB. The paper notes that axillary ultrasound was not routinely performed and magnetic resonance imaging was performed only for patients in whom breast-conserving surgery was considered. No mention is made in the paper of the role of these imaging Society of Surgical Oncology 2016

Her2 positivity and race predict higher mastectomy rates: a SEER database analysis

Given the difference in incidence of biologic subtype of breast cancer between black and white women, and the potential disparity in type of surgery in black and white women presenting with early stage breast cancer, this study aimed to examine the odds of mastectomy compared to lumpectomy by molecular subtype in black and white women with size T1 and T2 invasive breast cancer. Using the SEER database, breast operation choice for women over the age of 15 with T1 or T2 tumors between 2010 and 2012 were examined. Tumors were categorized according to the Breast Subtype variable in the SEER database and data were stratified by tumor size and race. Bivariate comparisons and logistic regression models adjusted for age were used. In women with T1 or T2 tumors, mastectomy rates were higher in women with Her2 positive tumors than in those with Her2 negative tumors. When Her2 results are the same among comparison groups, those women with HR positive tumors were less likely to undergo a mastectomy than those with HR negative tumors. In T1 tumors, the magnitude of the association was larger for white women than women of other races. Results suggest there are differences in surgical decision making based on breast cancer subtype in women with T1 or T2 tumors and that race may play a role for size T1 tumors. The strong association between Her2 positive tumors and higher mastectomy rates warrants further investigation.

Cytoreductive Surgery and Normothermic Intraperitoneal Chemotherapy for Signet Ring Cell Appendiceal Adenocarcinoma With Peritoneal Metastases in the Setting of Cirrhosis

Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are combined to treat peritoneal surface malignancies (PSM). The objective of cytoreduction is to eradicate macroscopic disease, while HIPEC addresses residual microscopic disease. Currently, there are no protocols guiding treatment of cirrhotic patients with PSM. We report the case of a cirrhotic patient with signet ring cell (SRC) appendiceal adenocarcinoma who underwent normothermic, as opposed to hyperthermic intraperitoneal chemotherapy (IPC). A 50-year-old woman with compensated class A cirrhosis and chronic hepatitis B and C underwent a right hemicolectomy in 2007 and adjuvant chemotherapy in 2008 for appendiceal SRC adenocarcinoma. In 2011, she was found to have peritoneal disease after a laparotomy. She subsequently experienced intolerance to chemotherapy, with stable disease on serial restaging. In light of her cirrhosis, the decision was made to perform CRS and IPC without hyperthermia to treat her residual disease. In 2012, she underwent CRS (omentectomy, total abdominal hysterectomy, left salpingo-oophorectomy) and IPC with mitomycin C. Thirty-day postoperative morbidity included delayed abdominal closure (Clavien-Dindo Grade IIIb), prolonged ventilator support (IIIa), vasopressor requirements (II), and confusion (II). The patient’s liver function remained stable. Eight months later, she had evidence of recurrence on computed tomography. Twenty-two months later, she developed an extrinsic compression secondary to evolving disease, requiring a palliative endoscopic stent. The patient expired from her disease 29 months after her CRS and IPC. The criteria guiding selection of suitable candidates for CRS continues to evolve. Concomitant compensated cirrhosis in patients with PSM should not constitute a reason independently to exclude CRS with intraperitoneal chemotherapy, given the oncologic benefits of the procedure.