Sanjay P. Bagaria

FOXC1 Is a Potential Prognostic Biomarker with Functional Significance in Basal-like Breast Cancer

Gene expression signatures for a basal-like breast cancer (BLBC) subtype have been associated with poor clinical outcomes, but a molecular basis for this disease remains unclear. Here, we report overexpression of the transcription factor FOXC1 as a consistent feature of BLBC compared with other molecular subtypes of breast cancer. Elevated FOXC1 expression predicted poor overall survival in BLBC (P = 0.0001), independently of other clinicopathologic prognostic factors including lymph node status, along with a higher incidence of brain metastasis (P = 0.02) and a shorter brain metastasis-free survival in lymph node-negative patients (P < 0.0001). Ectopic overexpression of FOXC1 in breast cancer cells increased cell proliferation, migration, and invasion, whereas shRNA-mediated FOXC1 knockdown yielded opposite effects. Our findings identify FOXC1 as a theranostic biomarker that is specific for BLBC, offering not only a potential prognostic candidate but also a potential molecular therapeutic target in this breast cancer subtype.

Management of Recurrent Retroperitoneal Sarcoma (RPS) in the Adult: A Consensus Approach from the Trans-Atlantic RPS Working Group

IntroductionRetroperitoneal soft tissue sarcomas (RPS) are rare tumors. Surgery is the mainstay of curative therapy, but local recurrence is common. No recommendations concerning the best management of recurring disease have been developed so far. Although every effort should be made to optimize the initial approach, recommendations to treat recurring RPS will be helpful to maximize disease control at recurrence.MethodsAn RPS transatlantic working group was established in 2013. The goals of the group were to share institutional experiences, build large multi-institutional case series, and develop consensus documents on the approach to this difficult disease. The outcome of this document applies to recurrent RPS that is nonvisceral in origin. Included are sarcomas of major veins, undifferentiated pleomorphic sarcoma of psoas, ureteric leiomyosarcoma (LMS). Excluded are desmoids-type fibromatosis, angiomyolipoma, gastrointestinal stromal tumors, sarcomas arising from the gut or its mesentery, uterine LMS, prostatic sarcoma, paratesticular/spermatic cord sarcoma, Ewing sarcoma, alveolar/embryonal rhabdomyosarcoma, sarcoma arising from teratoma, carcinosarcoma, sarcomatoid carcinoma, clear cell sarcoma, radiation-induced sarcoma, paraganglioma, and malignant pheochromocytoma.ResultsRecurrent RPS management was evaluated from diagnosis to follow-up. It is a rare and complex malignancy that is best managed by an experienced multidisciplinary team in a specialized referral center. The best chance of cure is at the time of primary presentation, but some patients may experience prolonged disease control also at recurrence, when the approach is optimized and follows the recommendations contained herein.ConclusionsInternational collaboration is critical for adding to the present knowledge. A transatlantic prospective registry has been established.

Does metastasectomy improve survival in patients with Stage IV melanoma? A cancer registry analysis of outcomes.

Patients with Stage IV melanoma have limited therapeutic options with few long‐term survivors. Our goal was to study the impact of metastasectomy on survival in these patients.

Sentinel Node Biopsy in Melanoma: Technical Considerations of the Procedure as Performed at the John Wayne Cancer Institute

Since its first description in 1990, sentinel node (SN) biopsy has become the standard for accurate staging of a melanoma‐draining regional lymphatic basin. This minimally invasive, multidisciplinary technique can detect occult metastases by selective sampling and focused pathologic analysis of the first nodes on the afferent lymphatic pathway from a primary cutaneous melanoma. An understanding of preoperative lymphoscintigraphy, intraoperative lymphatic mapping, and the definition of SN are critical for surgical expertise with SN biopsy. J. Surg. Oncol. 2010; 101:669‐676.

Lichenoid dermatitis in three patients with metastatic melanoma treated with anti-PD-1 therapy.

Joseph and colleagues describe the immunemediated rash, lichenoid dermatitis, in three patients treated with anti–PD-1 (MK-3475). These mild rashes are characterized by a marked T-cell infiltrate with ∼10% PD-1+ T cells. Therapies that activate the immune system through blocking the binding of programmed death ligand 1 (PD-L1) present on tumors and PD-1 (programmed death 1) present on activated immune cells are revolutionizing the care for patients with cancer. These therapies work by inhibiting negative regulators of the immune system, thereby decreasing a tumors ability to evade the immune system. The side effects of anti–PD-1/PD-L1 therapies are generally mild and as expected are related to autoimmune reactions. Two of the most common side effects of anti–PD-1/PD-L1 therapies are rash and pruritus occurring in approximately 20% of patients. Although the rash is generally recognized to be immune mediated, the exact mechanisms of the rash remain unclear. Herein, we report three cases of lichenoid dermatitis in three patients treated with MK-3475 (anti–PD-1) that were characterized with marked T-cell infiltrates with few PD-1–positive cells. The rashes in all three patients were relatively mild, allowing treatment to continue despite the rashes. Cancer Immunol Res; 3(1); 18–22. ©2014 AACR.

FOXC1 regulates the functions of human basal-like breast cancer cells by activating NF-κB signaling

Human basal-like breast cancer (BLBC) is an enigmatic and aggressive malignancy with a poor prognosis. There is an urgent need to identify therapeutic targets for BLBC, because current treatment modalities are limited and not effective. The forkhead box transcription factor FOXC1 has recently been identified as a critical functional biomarker for BLBC. However, how it orchestrates BLBC cells was not clear. Here we show that FOXC1 activates the transcription factor nuclear factor-κB (NF-κB) in BLBC cells by increasing p65/RelA protein stability. High NF-κB activity has been associated with estrogen receptor-negative breast cancer, particularly BLBC. The effect of FOXC1 on p65/RelA protein stability is mediated by increased expression of Pin1, a peptidyl-prolyl isomerase. FOXC1 requires NF-κB for its regulation of cell proliferation, migration and invasion. Notably, FOXC1 overexpression renders breast cancer cells more susceptible to pharmacological inhibition of NF-κB. These results suggest that BLBC cells may rely on FOXC1-driven NF-κB signaling. Interventions of this pathway may provide modalities for the treatment of BLBC.

Trends in Risk Reduction Practices for the Prevention of Lymphedema in the First 12 Months after Breast Cancer Surgery

BACKGROUND Lymphedema is a feared complication of breast cancer surgery. We evaluated the trends in lymphedema development, patient worry, and risk reduction behaviors. STUDY DESIGN We prospectively enrolled 120 women undergoing sentinel node biopsy (SLNB) or axillary node dissection (ALND) for breast cancer and assessed lymphedema by upper extremity volume preoperatively and at 6 and 12 months postoperatively. We defined lymphedema as a >10% volume change from baseline relative to the contralateral upper extremity. Patients completed a validated instrument evaluating lymphedema worry and risk reducing behaviors. Associations were determined by Fishers exact and signed rank tests. RESULTS At 6 months, lymphedema was similar between ALND and SLNB patients (p = 0.22), but was higher in ALND women at 12 months (19% vs 3%, p = 0.005). A clear relationship exists between relative change in upper extremity volume at 6 and 12 months (Kendall tau coefficient 0.504, p < 0.001). Among the women with 0 to 9% volume change at 6 months, 22% had progressive swelling, and 18% resolved their volume changes at 12 months. Overall, 75% of ALND and 50% of SLNB patients had persistent worry about lymphedema at follow-up, and no difference existed in the number of risk reducing behaviors practiced among the 2 groups (p > 0.34). CONCLUSIONS Upper extremity volumes fluctuate, and there is a period of latency before development of lymphedema. Despite the low risk of lymphedema after SLNB, most women worry about lymphedema and practice risk reducing behaviors. Additional study into early upper extremity volume changes is warranted to allay the fears of most women and better predict which women will progress to lymphedema.

Personalizing breast cancer staging by the inclusion of ER, PR, and HER2

IMPORTANCE Nonanatomic factors, such as histologic grade and biomarkers, can guide breast cancer management but are not included in the current TNM staging system. OBJECTIVE To use as an example the triple-negative phenotype (TNP) defined by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor 2 (HER2) to examine whether such inclusion improves the prognostic accuracy of TNM staging for breast cancer. DESIGN, SETTING, AND PARTICIPANTS Women diagnosed with primary invasive ductal breast cancer from January 1, 1991, through December 31, 2008, were identified from a prospective institutional database. Excluded were patients who received neoadjuvant therapy, those whose staging information was incomplete, or those whose tumor lacked ER, PR, and HER2 data. Breast cancers were categorized by TNM stage and by the presence or absence of TNP. MAIN OUTCOMES AND MEASURES Overall survival at 5 years. RESULTS Database review identified 1842 consecutive eligible patients with breast cancer. When patients were stratified by TNM stage, overall survival curves for those with TNP breast cancer matched those for patients whose non-TNP breast cancer was 1 TNM stage higher. Multivariable analysis showed that TNP status was a powerful prognostic variable, and the likelihood ratio test revealed that the prognostic accuracy of the TNM staging system that incorporated TNP was superior to the current TNM staging system (P< .001). A TNM staging system that incorporated TNP reduced early-stage compression by 15%. CONCLUSIONS AND RELEVANCE The internationally recognized and easily reproducible examination of ER, PR, and HER2 status exemplifies how nonanatomic factors can improve the prognostic accuracy of breast cancer staging.

Validation of the Updated 7th Edition AJCC TNM Staging Criteria for Gastric Adenocarcinoma

IntroductionThe recently published 7th edition of the American Joint Committee on Cancer (AJCC) TNM staging criteria for gastric adenocarcinoma contains important revisions to T and N classifications, as well as overall stage grouping. Our goal was to validate the new staging system using a cancer registry.MethodsRetrospective review of gastric cancer patients from Surveillance, Epidemiology, and End Results (SEER) registry data (2004–2007). Patients were staged according to both 6th and 7th edition criteria, and 3-year disease-specific survival was compared.ResultsThirteen thousand five hundred forty-seven patients with gastric adenocarcinoma were identified with complete staging information. When using 7th edition criteria, there was an increase in the number of patients classified as stage III (23% vs. 13%), and a decrease in patients classified as stage IV (47% vs. 53%). Statistically significant differences in 3-year disease-specific survival were observed for all T and N categories and re-staging the same population according to the 7th edition criteria improved survival discrimination. Multivariate analysis revealed statistically significant differences in survival and linear progression of hazard ratios for each stage grouping.ConclusionsThe 7th edition AJCC staging criteria for gastric adenocarcinoma demonstrate better survival discrimination and risk stratification than previous criteria.

Diagnosis of Basal-Like Breast Cancer Using a FOXC1-Based Assay

BACKGROUND Diagnosis of basal-like breast cancer (BLBC) remains a bottleneck to conducting effective clinical trials for this aggressive subtype. We postulated that elevated expression of Forkhead Box transcription factor C1 (FOXC1) is a simple and accurate diagnostic biomarker for BLBC. METHODS Accuracy of FOXC1 expression in identifying BLBC was compared with the PAM50 gene expression panel in gene expression microarray (GEM) (n = 1992) and quantitative real-time polymerase chain reaction (qRT-PCR) (n = 349) datasets. A FOXC1-based immunohistochemical (IHC) assay was developed and assessed in 96 archival formalin-fixed, paraffin-embedded (FFPE) breast cancer samples that also underwent PAM50 profiling. All statistical tests were two-sided. RESULTS A FOXC1-based two-tier assay (IHC +/- qRT-PCR) accurately identified BLBC (AUC = 0.88) in an independent cohort of FFPE samples, validating the accuracy of FOXC1-defined BLBC in GEM (AUC = 0.90) and qRT-PCR (AUC = 0.88) studies, when compared with platform-specific PAM50-defined BLBC. The hazard ratio (HR) for disease-specific survival in patients having FOXC1-defined BLBC was 1.71 (95% CI = 1.31 to 2.23, P < .001), comparable to PAM50 assay-defined BLBC (HR = 1.74, 95% CI = 1.40 to 2.17, P < .001). FOXC1 expression also predicted the development of brain metastasis. Importantly, unlike triple-negative or Core Basal IHC definitions, a FOXC1-based definition is able to identify BLBC in both ER+ and HER2+ patients. CONCLUSION A FOXC1-based two-tier assay, by virtue of being rapid, simple, accurate, and cost-effective may emerge as the diagnostic assay of choice for BLBC. Such a test could substantially improve clinical trial enrichment of BLBC patients and accelerate the identification of effective chemotherapeutic options for this aggressive disease.