Sara H. Javid

Apc Deficiency Is Associated with Increased Egfr Activity in the Intestinal Enterocytes and Adenomas of C57BL/6J-Min/+ Mice

Overexpression of the epidermal growth factor receptor (EGFR) and its increased tyrosine kinase activity are implicated in colorectal cancer (CRC) development and malignant progression. The C57BL/6J-Min/+ (Min/+) mouse is a model for CRC and develops numerous intestinal adenomas. We analyzed the normal mucosa of Min/+ and Apc+/+ (WT) littermate mice together with Apc-null adenomas to gain insight into the roles of Egfr in these intestinal tissues. Protein analyses showed that Egfr activity was highest in the tumors, and also up-regulated in Min/+ relative to WT enterocytes. Expression of ubiquitylated Egfr (Egfr-Ub) was increased in Min/+ enterocytes and tumors. Tumors exhibited increased association of Egfr with clathrin heavy chain (CHC), Gab1, and p85α, the regulatory subunit of phosphoinositide 3-kinase (PI3K), and tumors also overexpressed c-Src, PDK1, and Akt. Immunohistochemistry for Akt-p-Ser473 revealed a low level of this active kinase in Min/+ and WT enterocytes and its strong presence in tumors. Prostaglandin E2 (PGE2) is a product of cyclooxygenase-2 (Cox-2) activity that is up-regulated in Min/+ tumors and transactivates Egfr. PGE2 expression was significantly higher in untreated Min/+ tumors and reduced by treatment with the Cox-2 inhibitor, celecoxib. Dietary administration of this NSAID also inhibited Egfr activity in tumors. Increased activation of the EGFR-PI3K-Akt signaling pathway in tumors relative to Apc+/+ and ApcMin/+ enterocytes provides potential opportunities for therapeutic interventions to differentially suppress tumor formation, promotion, progression, and/or recurrence.

Estrogen Receptors α and β Are Inhibitory Modifiers of Apc-Dependent Tumorigenesis in the Proximal Colon of Min/+ Mice

Estrogen replacement therapy in postmenopausal women is associated with a reduction in colorectal cancer risk, potentially via interactions between 17β-estradiol (E2) and the estrogen receptors (ER) α and β. To study the role of E2 in intestinal tumor inhibition, we separately crossed C57BL/6J-Min/+ (Min/+) mice with Erα +/− and Erβ +/− mice to generate ER -deficient Min/+ progeny. We found an increased incidence of visible colon tumors and dysplastic microadenomas in ER -deficient Min/+ relative to Er +/+Min/+ controls. Small intestinal tumor numbers were unaffected. Invasive carcinomas were found only in Erα +/−Min/+ mice, suggesting that ERα plays additional non–cell autonomous roles that limit tumor progression. Histologic analyses of ER-deficient Min/+ colons, as well as colons from ovariectomized Min/+ mice (OvxMin/+) and E2-treated OvxMin/+ mice (OvxMin/+ +E2), revealed significant differences in crypt architecture, enterocyte proliferation, and goblet cell differentiation relative to Min/+ and Er +/+ Apc +/+ (wild-type) controls. The expression of ERα and ERβ was regionally compartmentalized along the colonic crypt axis, suggesting functional antagonism. Our results indicate that ERα and ERβ are inhibitory modifiers of Apc -dependent colon tumorigenesis. As a result, loss of E2 and ER signaling in postmenopausal women may contribute to colorectal cancer development. [Cancer Res 2007;67(5):2366–72]

Imaging Axillary Lymph Nodes in Patients with Newly Diagnosed Breast Cancer

The presence of axillary lymph node metastasis in patients newly diagnosed with breast cancer carries significant prognostic and management implications. As a result, there is increasing interest to stage accurately the axilla with preoperative imaging to facilitate treatment planning. Currently, the most widespread imaging techniques for the evaluation of the axilla include ultrasound and magnetic resonance imaging. In many settings, the ability to detect axillary lymph nodes containing metastases with imaging and image-guided biopsy can allow surgeons to bypass sentinel lymph node dissection and proceed with full axillary lymph node dissection. However, no imaging modality currently has sufficient negative-predictive value to obviate surgical staging of the axilla if no abnormal lymph nodes are detected. Promising advanced imaging technologies, such as diffusion-weighted imaging and magnetic resonance lymphangiography, hold the potential to improve the accuracy of axillary staging and thereby transform management of the axilla in patients newly diagnosed with breast cancer.

Can Breast MRI Predict Axillary Lymph Node Metastasis in Women Undergoing Neoadjuvant Chemotherapy

BackgroundAxillary lymph node status provides important staging information. We sought to evaluate the predictive value of breast magnetic resonance imaging (MRI) in detecting axillary lymph node metastases prior to initiation of neoadjuvant chemotherapy (NAC) and in detecting residual lymph node metastases after NAC in women found to be node positive prior to NAC.MethodsWomen underwent breast MRI with axillary evaluation prior to initiation of NAC and again after completion of NAC. Pathologic confirmation of lymph node status was confirmed by sentinel lymph node biopsy (SLNB), image-guided axillary fine-needle aspiration (FNA)/core biopsy, or axillary lymph node dissection. We evaluated the sensitivity, specificity, and negative and positive predictive values of MRI in detecting axillary node involvement.ResultsSeventy-four women completed NAC and underwent surgery. Sensitivity of MRI in detecting axillary node involvement prior to NAC was 64.7% and specificity was 100%, with positive and negative predictive values of MRI of 100% and 77.8%, respectively. Sensitivity and specificity of MRI to identify residual pathologic axillary lymph node disease following NAC were 85.7% and 89%, respectively, while the positive and negative predictive values were 92% and 80.9%, respectively.ConclusionBreast MRI has moderate sensitivity and high specificity for predicting axillary lymph node status prior to NAC. In patients found to be node positive prior to NAC, MRI was able to predict with moderate sensitivity and specificity whether residual nodal disease was present. The accuracy of MRI is not adequate to obviate either the need for staging by sentinel node biopsy or the need for completion axillary dissection in women determined to be node positive prior to NAC.

Tubular carcinoma of the breast: results of a large contemporary series

BACKGROUND Tubular carcinoma (TC) of the breast is an uncommon subtype associated with a favorable prognosis. This study aimed to assess recent trends and prognostic features in the treatment of TC. METHODS We performed a retrospective review of cases of TC of the breast treated between 1997 and 2004. RESULTS We identified 111 cases of TC of the breast. The median patient age at diagnosis was 55 years, and the median follow-up period was 72 months. Breast-conservation surgery was performed in 75% (83 of 111) of patients. Axillary staging was performed in 80% (89 of 111). Nine (8.1%) were found to be node-positive. Node positivity was associated with larger tumor size (P = .003). All node-positive tumors were greater than 1 cm. One patient developed an in-breast recurrence. No patient developed distant metastases or died from breast cancer. CONCLUSIONS In this series of TC, the locoregional recurrence rate was low and no patient developed distant metastases. Surgical staging of the axilla may not be necessary in lesions measuring 1 cm or less.

Quantitative molecular phenotyping with topically applied SERS nanoparticles for intraoperative guidance of breast cancer lumpectomy

There is a need to image excised tissues during tumor-resection procedures in order to identify residual tumors at the margins and to guide their complete removal. The imaging of dysregulated cell-surface receptors is a potential means of identifying the presence of diseases with high sensitivity and specificity. However, due to heterogeneities in the expression of protein biomarkers in tumors, molecular-imaging technologies should ideally be capable of visualizing a multiplexed panel of cancer biomarkers. Here, we demonstrate that the topical application and quantification of a multiplexed cocktail of receptor-targeted surface-enhanced Raman scattering (SERS) nanoparticles (NPs) enables rapid quantitative molecular phenotyping (QMP) of the surface of freshly excised tissues to determine the presence of disease. In order to mitigate the ambiguity due to nonspecific sources of contrast such as off-target binding or uneven delivery, a ratiometric method is employed to quantify the specific vs. nonspecific binding of the multiplexed NPs. Validation experiments with human tumor cell lines, fresh human tumor xenografts in mice, and fresh human breast specimens demonstrate that QMP imaging of excised tissues agrees with flow cytometry and immunohistochemistry, and that this technique may be achieved in less than 15 minutes for potential intraoperative use in guiding breast-conserving surgeries.

High Cancer Yield and Positive Predictive Value: Outcomes at a Center Routinely Using Preoperative Breast MRI for Staging

OBJECTIVE The purpose of our study is to report the outcomes at a center that routinely uses breast MRI for preoperative staging, regardless of lesion histology or patient characteristics. MATERIALS AND METHODS Five hundred ninety-two patients with recently diagnosed breast cancer who underwent staging with preoperative breast MRI between January 1, 2003, and April 30, 2007, were reviewed. Five hundred seventy patients comprised the analysis set. Patient age, breast density, index tumor histology, receptor status (ER, PR, and HER2), and lymph node status were recorded. Biopsy rates, positive predictive values (PPVs) of biopsy, and overall cancer yield were calculated and compared using the chi-square test across patient age, mammographic breast density, index tumor type, receptor status, and lymph node status. RESULTS Biopsy was recommended and performed for 152 of 570 (27%) patients found to have one or more suspicious lesions on MRI distinct from the index cancer. Sixty-seven of 152 women who underwent biopsy had additional cancers diagnosed, for a PPV of 44%. Overall, 12% (67/570) of women had otherwise occult cancers diagnosed by MRI, with 8% having additional sites or greater extent of ipsilateral disease and 4% having unsuspected contralateral cancer detected by MRI alone. No significant differences were found in the probability of detecting an occult cancer on the basis of patient age, breast density, index tumor characteristics, or lymph node status. CONCLUSION Breast MRI detects otherwise occult cancer with an overall added cancer yield of 12% and a high PPV of 44% when applied to a diverse population of patients with newly diagnosed breast cancer.

Do sentinel node micrometastases predict recurrence risk in ductal carcinoma in situ and ductal carcinoma in situ with microinvasion

BACKGROUND Because the implications of micrometastases found on sentinel node biopsy (SNB) for ductal carcinoma in situ (DCIS) or ductal carcinoma in situ with microinvasion (DCISM) are largely unknown, we wished to determine if SNB pathology predicted recurrence risk in DCIS/DCISM. METHODS Retrospective chart review identified patients with DCIS/DCISM who underwent SNB. SNB findings and all local and distant recurrences were determined. RESULTS A total of 322 patients underwent SNB for DCIS/DCISM. There were 13 local recurrences (4.0%) and 1 (.03%) distant recurrence at a median follow-up of 47.9 months (range 0 to 110.6), 12 in patients with negative SNBs; 1 patient had a positive SNB. There were 4 recurrences after mastectomy and 9 after lumpectomy. In 29 patients with positive SNBs, there was only 1 recurrence (3.4%). CONCLUSIONS Positive SNBs in patients with DCIS or DCISM are not associated with higher risk of local or distant recurrence. Other features of DCIS and DCISM may be important in predicting recurrence risk.

Guideline‐concordant cancer care and survival among American Indian/Alaskan Native patients

American Indians/Alaskan Natives (AI/ANs) have the worst 5‐year cancer survival of all racial/ethnic groups in the United States. Causes for this disparity are unknown. The authors of this report examined the receipt of cancer treatment among AI/AN patients compared with white patients.

Mounting Evidence Against Complex Decongestive Therapy As a First-Line Treatment for Early Lymphedema

Arm lymphedema is a feared and presently incurable complication of breast cancer surgery and radiation treatment (RT). Lymphedema results from excess interstitial fluid accumulation, which leads to limb swelling and eventual tissue fibrosis that can cause lifelong impairment of arm use. Lymphedema concerns take center stage at many, if not the majority, of preoperative and postoperative consultations with patients who are undergoing breast cancer surgery, given that this complication can permanently harm quality of life, from both a physical/functional perspective as well as a psychosocial one. Findings from a 2013 systematic review and meta-analysis of 72 studies revealed an estimated 17% risk of arm lymphedema among patients with breast cancer, with risk increasing up to 2 years after surgery. The risk was four times higher in women who had a complete axillary lymph node dissection (ALND; 20%) versus those who had sentinel lymph node biopsy alone (5.6%). Among women who receive adjuvant RT after ALND, lymphedema risk is significantly higher. In a 2001 systematic review, the rate of lymphedema among women who underwent surgery plus axillary RT was an alarming 41%. Aside from treatment-related risk factors, a number of patient or disease-related risk factors exist for the development of lymphedema. Postoperative infection or delayed wound healing is associated with heightened lymphedema risk. A much more prevalent risk factor is obesity (body mass index 30 kg/m), which portends a nearly three-fold increase in risk for lymphedema. According to 2009/2010 Centers for Disease Control and Prevention statistics, 36% of all women and 42% of women age 60 years or older are obese in the United States. In the current era, with widening adoption of the findings of the American College of Surgeons Oncology Group (ACOSOG) Z0011 trial, incidence of lymphedema should decline, given that we see decreasing rates of completion ALND among a subset of women undergoing breast-conserving therapy. However, there remains a large population of patients with node-positive disease for whom ALND is still indicated, including those with clinically positive nodes, locally advanced disease, those receiving neoadjuvant chemotherapy, and those undergoing mastectomy. Hence, research into the treatment of this chronic condition remains an important public health issue. Because many lymphedema risk factors are not modifiable, attention has largely been directed at treatment. To this aim, a number of studies have compared efficacy of various treatment options for lymphedema. Treatment options include, alone or in combination, exercise, skin care, compression bandaging, compression garments, manual therapy (massage), laser therapy, and pneumatic pumps. Complex decongestive therapy (CDT) incorporates manual lymphatic drainage, daily bandaging, exercise, and skin care. A systematic review of these therapies was published in 2006 and found that, in general, more intensive treatment by health professionals, such as CDT or manual lymphatic drainage, produced larger volume reductions than therapies undertaken by the patient, such as compression bandaging, exercise, or skin care. Studies of CDT showed an estimated 43% reduction in arm volume compared with only 11% with compression alone. However, excitement over CDT has been tempered by subsequent randomized trials that have thus far failed to demonstrate a significant benefit of CDT over standard compression therapy. In one trial by McNeely et al, 50 women were randomly assigned to 4 weeks of CDT or compression alone. Arm volume decreased significantly with both treatments, but no difference was observed between groups (46% CDT v 39% compression alone; P .22). This study was limited in follow-up to 1 month and did not assess quality-of-life parameters associated with treatment of lymphedema. Another trial by Andersen et al randomly assigned 42 women with lymphedema to CDT versus compression, and observed patients for 12 months. They also found no significant difference in arm volume reduction over the 12-month period between CDT and compression groups (48% v 60%, respectively; P .66). Armed with these data, one might question why yet another randomized controlled trial was necessary to examine this question. Limitations of the above trials included their small size, singleinstitution setting (and sometimes, even single CDT provider), and lack of long-term follow-up. In the article that accompanies this editorial, Dayes et al address all of these limitations in their eloquently designed, randomized, multicenter trial of CDT versus compression bandaging alone for patients with lymphedema. Dayes et al randomly assigned 103 women from six Canadian cancer centers to either CDT or compression bandaging between 2003 and 2009. Type and duration of CDT were standardized across groups, as were arm measurement techniques. Diary logs were JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 31 NUMBER 30 OCTOBER 2