Trends in utilization of hypofractionated whole breast irradiation (HF-WBI) in triple negative breast cancer (TNBC): a national cancer database (NCDB) analysis.

PURPOSE: We sought to identify trends over time with respect to the use of hypofractionated whole breast irradiation (HF-WBI) in women with triple negative breast cancer (TNBC) in the national cancer database (NCDB). METHODS: Trends in utilization of HF-WBI in women diagnosed with T1-2N0 TNBC in the NCDB between 2008 and 2013 were analyzed. Case-matched luminal A women were used for comparison. Variables included age, race, year of diagnosis, insurance status, income quartile, receipt of neoadjuvant chemotherapy, and institution (academic vs. community). Chi square, logistic regression, and multivariate analysis was performed. RESULTS: Utilization of HF-WBI among the 53,269 TNBC women identified steadily increased from 4.7% in 2008 to 14.0% in 2013 for women with TNBC compared to luminal A cancer whose utilization increased from 7.3 to 23.3% over the same time frame (p < 0.001). On univariate analysis, HF-WBI was associated with increasing age (p < 0.001), Medicare insurance (p < 0.001), race (p = 0.041), diagnosis after 2011 (p < 0.001), higher income quartile (p < 0.001), and treatment at academic institutions (p < 0.001). On multivariate analysis, age (p < 0.001, OR 1.038 per year), income quartile (p = 0.002, OR 1.061 per increase in quartile), treatment at an academic institution (p < 0.001, OR 1.78) significantly increased use of HF-WBI. CONCLUSIONS: Treatment at an academic center and year of diagnosis were most correlated with increased HF-WBI in T1-2N0 TNBC women in the NCDB from 2008 to 2013, followed by increasing age and income. Only 14% of T1-2N0 TNBC women received HF-WBI in 2013. Focus on increased utilization is needed for non-academic centers, lower income, and younger women.

Utilization of hypofractionated whole-breast radiation therapy in patients receiving chemotherapy: a National Cancer Database analysis.

PURPOSE: Results from four major hypofractionated whole-breast radiotherapy (HF-WBRT) trials have demonstrated equivalence in select patients with early-stage breast cancer when compared with conventionally fractionated WBRT (CF-WBRT). Because relatively little data were available on patients receiving neoadjuvant or adjuvant chemotherapy, consensus guidelines published in 2011 did not endorse the use of HF-WBRT in this population. Our goal is to evaluate trends in utilization of HF-WBRT in patients receiving chemotherapy. METHODS AND MATERIALS: We retrospectively analyzed data from 2004 to 2013 in the National Cancer DataBase on breast cancer patients treated with HF-WBRT who met the clinical criteria proposed by consensus guidelines (i.e., age >0 years, T1-2N0, and breast-conserving surgery), regardless of receipt of chemotherapy. We employed logistic regression to delineate and compare clinical and demographic factors associated with utilization of HF-WBRT and CF-WBRT. RESULTS: A total of 56,836 women were treated with chemotherapy and WBRT (without regional nodal irradiation) from 2004 to 2013; 9.0% (n = 5093) were treated with HF-WBRT. Utilization of HF-WBRT increased from 4.6% in 2004 to 18.2% in 2013 (odds ratio [OR] 1.21/year; P < 0.001). Among patients receiving chemotherapy, factors most dramatically associated with increased odds of receiving HF-WBRT on multivariate analysis were academic facilities (OR 2.07; P < 0.001), age >80 (OR 2.58; P < 0.001), west region (OR 1.91; P < 0.001), and distance >50 miles from cancer reporting facility (OR 1.43; P < 0.001). Factors associated with decreased odds of receiving HF-WBRT included white race, income <$48,000, lack of private insurance, T2 versus T1, and higher grade (all P < 0.02). CONCLUSIONS: Despite the absence of consensus guideline recommendations, the use of HF-WBRT in patients receiving chemotherapy has increased fourfold (absolute = 13.6%) over the last decade. Increased utilization of HF-WBRT should result in institutional reports verifying its safety and efficacy.

Increasing utilization of regional nodal irradiation in elderly node-positive women and declining emphasis on demographic factors.

PURPOSE: To evaluate the practice patterns for the use of regional nodal irradiation (RNI) in treatment of elderly women with low volume node-positive breast cancer in the setting of breast conservation surgery (BCS). METHODS: Women aged 70-89 diagnosed with unilateral, pathologic T1-2N1M0 breast cancer from 2004 to 2013, who underwent BCS and received radiotherapy were identified from the National Cancer Database. In 2011, two major trials were presented that helped define indications for RNI. Patients were dichotomized into "early", i.e. diagnosed up to 2010, and "late" cohorts. Patient and treatment characteristics were compared between the cohorts and logistic regression used to determine independent factors associated with the receipt of RNI. RESULTS: 7228 women met inclusion criteria; 4330 (59.9%) in early and 2898 (40.1%) in late cohorts. Utilization of RNI increased from 33.9% in early to 42.5% in late cohorts (P ≤ 0.001) and was independent of a general increase in RNI utilization. RNI in the early and late cohorts was not different between the study population and younger women (P > 0.05). RNI utilization increased in both cohorts with increasing number of positive lymph nodes. In the early cohort, RNI was also associated with higher grade, white race and lower income. In the late cohort, RNI increased with the presence of multiple, predefined risk factors. CONCLUSIONS: There was an increase in utilization of RNI for elderly patients from 2004 to 2013. In more recent years, the primary factors associated with receipt of RNI were tumor related with declining importance of demographic factors.

Factors Influencing Management and Outcome in Patients with Occult Breast Cancer with Axillary Lymph Node Involvement: Analysis of the National Cancer Database.

BACKGROUND: Occult breast cancer (OBC) is rare and optimal local-regional (LR) management has not been defined. Using a patient registry database, we examine factors associated with treatment and outcomes in OBC. METHODS: Female patients with cT0 N1/2 M0 BC were selected from the National Cancer Database (2004-2013) and categorized into four treatment groups: MAST = mastectomy with axillary lymph node dissection (ALND) ± radiation (RT); RT + ALND = RT with ALND, no breast surgery; ALND = ALND alone; OBS = no breast surgery, RT, or ALND. Patient characteristics and overall survival (OS) were compared between groups, and multivariable analysis was used to identify factors associated with treatment and OS. RESULTS: Among 2.03 million BC cases, 1853 females (0.09%) with cT0 N1/2 M0 disease were identified and 1231 patients were categorized into a treatment group: MAST = 592, RT + ALND = 342, ALND = 106, OBS = 191. On logistic regression, care at an academic center was associated with a higher likelihood of RT + ALND compared with MAST (odds ratio 2.03, 95% confidence interval [CI] 1.50-2.74, p < 0.001). Patients treated with RT + ALND had significantly better OS on univariate survival analysis compared with patients treated with MAST (hazard ratio [HR] 0.475, 95% CI 0.306-0.736, p = 0.001). RT + ALND was independently associated with OS on multivariable survival analysis (HR 0.509, 95% CI 0.321-0.808, p = 0.004), after adjusting for covariates. CONCLUSIONS: Patients with OBC were more likely to undergo RT + ALND if they received care at an academic center. Patients treated with RT + ALND had significantly better OS compared with patients treated with MAST, after adjusting for covariates. This supports the use of RT + ALND as LR treatment for patients with OBC.

Weight loss with mindful eating in African American women following treatment for breast cancer: a longitudinal study.

PURPOSE: Women with higher body mass index (BMI) following breast cancer (BC) treatment are at higher risk of BC recurrence and death than women of normal weight. African American (AA) BC patients have the highest risk of BC recurrence and gain more weight after diagnosis than their white counterparts. The purpose of this study was to evaluate the association between a mindful eating intervention and weight loss in AA women following chemotherapy for BC. METHODS: A single-group 24-week longitudinal pilot study with repeated measures was conducted. AA women (N = 22, BMI = 35.13 kg/m(2), range = 27.08-47.21) with stage I-III BC who had finished active cancer treatment received a 12-week mindful eating intervention with individual dietary counseling and group mindfulness sessions, followed by bi-weekly telephone follow-up for 12 weeks. Linear mixed models were used to evaluate the effects of the intervention and of baseline mindfulness on the weight change over time. RESULTS: In the overall group (N = 22), MEQ scores increased over time (p = 0.001) while weight decreased over time (-0.887 kg, p = 0.015). Weight loss over time was associated with higher T1 MEQ scores (p = 0.043). Participants in the higher MEQ group (n = 11) at T1 experienced significant weight loss over time (-1.166 kg, p = 0.044), whereas those in the low MEQ (n = 11) did not lose weight. Participants who were diagnosed with stage 1 BC experienced significant weight loss over time (-7.909 kg, p = 0.014). CONCLUSIONS: This study suggests that a mindful weight loss program may be effective for weight reduction and maintenance in some AA women who have completed treatment for BC, particularly those diagnosed with stage 1 BC and with initially higher mindful eating behaviors. Mindful weight loss program is proposed as a promising way in which to reduce obesity-related conditions in AA BC survivors.

Invariant natural killer T cells generated from human adult hematopoietic stem-progenitor cells are poly-functional.

Invariant natural killer T (iNKT) cells constitute an important subset of T cells that can both directly and indirectly mediate anti-tumor immunity. However, cancer patients have a reduction in both iNKT cell number and function, and these deficits limit the potential clinical application of iNKT cells for cancer therapy. To overcome the problem of limited iNKT cell numbers, we investigated whether iNKT cells can be generated in vitro from bone marrow-derived adult hematopoietic stem-progenitor cells (HSPC). Our data demonstrate that co-culture of HSPC with OP9-DL1 stromal cells, results in a functional CD3(+) T cell population. These T cells can be further differentiated into iNKT cells by secondary culture with CD1d-Ig-based artificial antigen-presenting cells (aAPC). Importantly, these in vitro-generated iNKT cells are functional, as demonstrated by their ability to proliferate and secrete IFN-γ and GM-CSF following stimulation.

Trastuzumab-induced cardiomyopathy: incidence and associated risk factors in an inner-city population.

BACKGROUND: Although it is known that trastuzumab causes cardiotoxicity, its extent and reversibility are still in question. Earlier studies have not evaluated consecutive patients with reproducible nuclear ventriculography. OBJECTIVE: We sought to evaluate the baseline characteristics which predispose patients to increased risk of trastuzumab cardiotoxicity and to determine the natural history of the cardiotoxicity. METHODS AND RESULTS: Left ventricular ejection fraction (LVEF) was measured in 76 women aged 36-73 years who had been treated with trastuzumab at the University of Maryland Greenebaum Cancer Center. LVEF was determined at baseline and then 3, 6, 9, and 12 months after treatment initiation. Cardiotoxicity was defined as ≥ 16% decrease in LVEF or ≥ 10% decrease in LVEF to <50%. There were no differences in comorbidities, earlier treatment, or demographics between patients with and without trastuzumab-induced cardiomyopathy except that African Americans were more likely to develop decreased LVEF (P < .05). Twenty-one patients (28%) met criteria for cardiotoxicity. Four of those patients were continued on trastuzumab and 17 patients had therapy withheld at some point. Only 1 patient developed symptomatic heart failure requiring inpatient hospitalization. LVEF improved in most patients regardless of whether or not trastuzumab was continued. CONCLUSIONS: Decreased LVEF while undergoing trastuzumab therapy occurs frequently and is usually reversible. African Americans had a higher risk of developing decreased LVEF. These findings raise clinically important questions as to whether it is necessary to discontinue trastuzumab for asymptomatic decrease in LVEF and whether African Americans are more predisposed to a decrease in LVEF while receiving trastuzumab. Further studies carefully assessing LVEF should address these hypotheses.

A pilot study of FDG PET/CT detects a link between brown adipose tissue and breast cancer.

BACKGROUND: Breast cancer is the second most lethal cancer in women. Understanding biological mechanisms that cause progression of this disease could yield new targets for prevention and treatment. Recent experimental studies suggest that brown adipose tissue (BAT) may play a key role in breast cancer progression. The primary objective for this pilot study was to determine if the prevalence of active BAT in patients with breast cancer is increased compared to cancer patients with other malignancies. METHODS: We retrospectively analyzed data from 96 breast cancer patients who had FDG PET/CT scan for routine staging at the University of Maryland and 96 age- and weight-matched control female patients with other malignancies (predominantly colon cancer) who had undergone FDG PET/CT imaging on the same day. Data on the distribution (bilateral upper neck, supraclavicular and paraspinal regions) and intensity (SUVmax) of active BAT were evaluated by 2 Nuclear Medicine physicians, blinded to the clinical history. RESULTS: We found sufficient evidence to conclude that based on our sample data the prevalence of active BAT in breast cancer patients' group is significantly different from that in the control group. The estimated frequency of BAT activity was 3 fold higher in breast cancer patients as compared to controls with other cancers, (16.7% vs. 5.2%, respectively, p = 0.019). When patients were stratified by age in order to determine the possible impact of age related hormonal changes on active BAT among the younger women (≤ 55 years of age), 25.6% breast cancer patients exhibited BAT activity compared to only 2.8% in control women (p = 0.007). In contrast, among the older women (> 55 years of age), the prevalence of active BAT was similar among breast cancer and control women (10.7% vs 6.7%). CONCLUSIONS: In breast cancer patients prevalence of BAT activity on FDGPET/CT is 3-fold greater than in age- and body weight-matched patients with other solid tumor malignancies; this difference is particularly striking among younger women aged < =55. In summary, our retrospective clinical data provide support to pursue prospective clinical and translational studies to further define the role of BAT in breast cancer development and progression.

mTOR inhibitors: changing landscape of endocrine-resistant breast cancer.

Most breast cancer (BC) patients have tumors that express hormone receptors (HRs). Although endocrine therapy, such as aromatase inhibitors, is very effective, most patients with metastatic HR-positive (HR(+)) BC become resistant to endocrine therapy at some point in their treatment and subsequently require chemotherapy. The PI3K/mTOR pathway is often upregulated in endocrine-resistant BC patients and, therefore, has been one of the targets for development of new agents. Recently, a Phase III trial (BOLERO-2) in aromatase inhibitor-resistant BC patients showed a significant improvement in time to progression with the combination of everolimus and exemestane compared with exemestane alone, confirming the importance of the PI3K/mTOR pathway in endocrine-resistant BC. Side effects from mTOR inhibitors are manageable, but early detection and proactive management are required to ensure patients' safety, compliance and continuity of treatment. Thus, mTOR inhibitors offer a new hope and promise for patients with HR(+) BC.

A Prospective Trial of Single-Fraction Radiation to the Tumor Bed with a Novel Breast-Specific Stereotactic Radiation Therapy Device: The GammaPod.

Purpose: Radiation therapy for early-stage breast cancer is typically delivered in a hypofractionated regimen to the whole breast followed by a tumor bed boost. This results in a treatment course of approximately 4 weeks. In this study, the tumor bed boost was delivered in a single fraction as part of a safety and feasibility study for FDA clearance of the device. Methods and Materials: Eligible women with early-stage breast cancer underwent lumpectomy followed by radiation therapy. Patients underwent breast immobilization using a system specific to the GammaPod followed by CT simulation, boost treatment planning, and boost treatment delivery all in a single treatment day. Patients then started whole-breast radiation therapy within 1 week of the boost treatment. Patients and treatments were assessed for safety and feasibility. Acute toxicities were recorded. Results: A single-fraction boost of 8 Gy was delivered to the tumor bed before a course of whole-breast radiation. The GammaPod treatment was successfully delivered to 14 of 17 enrolled patients. Acute toxicities from all radiation therapy, inclusive of the boost and whole-breast radiation, were limited to grade 1 events. Conclusions: The GammaPod device successfully delivered a single-fraction boost treatment to the tumor bed with no change in expected acute toxicities. The results of this study led to FDA clearance of the device through the Investigational Device Exemption process at the FDA. The GammaPod is in clinical use at 4e institutions nationally and internationally, with additional sites pending in 2023.

Increasing national mastectomy rates for the treatment of early stage breast cancer.

BACKGROUND: To study national trends in the mastectomy rate for treatment of early stage breast cancer. METHODS: We analyzed data from the Surveillance, Epidemiology, and End Results database, including 256,081 women diagnosed with T1-2 N0-3 M0 breast cancer from 2000 to 2008. We evaluated therapeutic mastectomy rates by the year of diagnosis and performed a multivariable logistic regression analyses to determine predictors of mastectomy as the treatment choice. RESULTS: The proportion of women treated with mastectomy decreased from 40.1 to 35.6 % between 2000 and 2005. Subsequently, the mastectomy rate increased to 38.4 % in 2008 (p < 0.0001). Simple logistic regression models demonstrated that mastectomy rates between 2005 and 2008 were moderated by age (p < 0.0001), marital status (p = 0.0230), and geographic location (p < 0.0001). Multivariate logistic regression analysis found that age, race, marital status, geographic location, involvement of multiple regions of the breast, lobular histology, increasing T stage, lymph node positivity, increasing grade, and negative hormone receptor status were independent predictors of mastectomy. Additionally, multivariate analysis confirmed that women diagnosed in 2008 were more likely to undergo mastectomy than women diagnosed in 2005 (odds ratio 1.17, 95 % confidence interval 1.13 to 1.21, p < 0.0001). CONCLUSIONS: There is evidence of a reversal in the previously declining national mastectomy rates, with the mastectomy rate reaching a nadir in 2005 and subsequently rising. Further follow-up to confirm this trend and investigation to determine the underlying cause of this trend and its effect on outcomes may be warranted.

In-situ cryo-immune engineering of tumor microenvironment with cold-responsive nanotechnology for cancer immunotherapy.

Cancer immunotherapy that deploys the host's immune system to recognize and attack tumors, is a promising strategy for cancer treatment. However, its efficacy is greatly restricted by the immunosuppressive (i.e., immunologically cold) tumor microenvironment (TME). Here, we report an in-situ cryo-immune engineering (ICIE) strategy for turning the TME from immunologically "cold" into "hot". In particular, after the ICIE treatment, the ratio of the CD8+ cytotoxic T cells to the immunosuppressive regulatory T cells is increased by more than 100 times in not only the primary tumors with cryosurgery but also distant tumors without freezing. This is achieved by combining cryosurgery that causes "frostbite" of tumor with cold-responsive nanoparticles that not only target tumor but also rapidly release both anticancer drug and PD-L1 silencing siRNA specifically into the cytosol upon cryosurgery. This ICIE treatment leads to potent immunogenic cell death, which promotes maturation of dendritic cells and activation of CD8+ cytotoxic T cells as well as memory T cells to kill not only primary but also distant/metastatic breast tumors in female mice (i.e., the abscopal effect). Collectively, ICIE may enable an efficient and durable way to leverage the immune system for combating cancer and its metastasis.

Progranulin (GP88) tumor tissue expression is associated with increased risk of recurrence in breast cancer patients diagnosed with estrogen receptor positive invasive ductal carcinoma.

INTRODUCTION: GP88 (progranulin) has been implicated in tumorigenesis and resistance to anti-estrogen therapies for estrogen receptor positive (ER+) breast cancer. Previous pathological studies showed that GP88 is expressed in invasive ductal carcinoma (IDC), but not in normal mammary epithelial tissue, benign lesions or lobular carcinoma. Based on these results, the present study examines GP88 prognostic significance in association with recurrence and death risks for ER+ IDC patients. METHODS: Two retrospective multi-site clinical studies examined GP88 expression by immunohistochemistry (IHC) analysis of paraffin-embedded breast tumor tissue sections from ER+ IDC patients (lymph node positive and negative, stage 1 to 3) in correlation with patients' survival outcomes. The training study established a GP88 cut-off value associated with decreased disease-free (DFS) and overall (OS) survivals. The validation study verified the GP88 cut-off value and compared GP88 prognostic information with other prognostic factors, particularly tumor size, grade, disease stage and lymph node status in multivariate analysis. RESULTS: GP88 expression is associated with a statistically significant increase in recurrence risk for ER+ IDC patients. The training study established that GP88 3+ score was associated with decreased DFS (P = 0.0004) and OS (P = 0.0036). The independent validation study verified that GP88 3+ score was associated with a 5.9-fold higher hazard of disease recurrence and a 2.5-fold higher mortality hazard compared to patients with tumor GP88 < 3+. GP88 remained an independent risk predictor after considering age, ethnicity, nodal status, tumor size, tumor grade, disease stage, progesterone receptor expression and treatments. CONCLUSIONS: The survival factor GP88 is a novel prognostic biomarker, predictive of recurrence risk and increased mortality for non-metastatic ER+ IDC patients. Of importance, our data show that GP88 continues to be a prognostic factor even after five years. These results also provide evidence that GP88 provides prognostic information independent of tumor and clinical characteristics and would support prospective study to examine whether GP88 expression could help stratify patients with ER+ tumors for adjuvant therapy.

A culturally specific dietary plan to manage weight gain among African American breast cancer survivors: a feasibility study.

Breast cancer survival rates are lower in African Americans (AAs) than in Caucasians, owing in part to a higher prevalence of obesity in the former, which increases the risk of recurrence and mortality. The Women's Intervention Nutrition Study (WINS) found that Caucasian women who followed a low-fat eating plan experienced a lower rate of cancer recurrence than women who maintained their usual diets. The purpose of this study was to test the feasibility of a WINS plan tailored to the cultural needs of AA breast cancer survivors. This feasibility pilot study was conducted at a university National Cancer Institute-designated comprehensive cancer center outpatient clinic with AA breast cancer survivors. The culturally specific WINS (WINS-c) plan included eight individual counseling sessions, five educational group meetings, and follow-up telephone calls over a 1-year period. Outcome measures included dietary fat, triglyceride, insulin and glucose levels, and fruit and vegetable intake. Participants (n = 8) had a mean age of 61.1 years (standard error of the mean (SEM) 3.1 years) and a mean BMI of 32 kg/m(2) (SEM 4.25 kg/m)(2). Baseline daily fat consumption decreased from 64.6 g (range 36.8-119.6g) to 44.0 g (21.6-73.4g) at 52 weeks (p = 0.07). Mean daily consumption of fruits and vegetables increased by 36% and 15%, respectively. Mean triglyceride levels decreased at 12 months (p < 0.05). Sustained hyperinsulinemia was noted in most participants, including those without diabetes. Mean calcium and vitamin D consumption decreased over the 1-year study period. In AA breast cancer survivors, the WINS-c program resulted in a trend toward reduced fat consumption and may represent a sustainable approach in this population for improvement of diet quality after breast cancer.

Circulating Biomarkers in Breast Cancer.

Breast cancer management has progressed immensely over the decades, but the disease is still a major source of morbidity and mortality worldwide. Even with enhanced imaging detection and tissue biopsy capabilities, disease can progress on an ineffective treatment before additional information is obtained through standard methods of response evaluation, including the RECIST 1.1 criteria, widely used for assessment of treatment response and benefit from therapy.6 Circulating biomarkers have the potential to provide valuable insight into disease progression and response to therapy, and they can serve to identify actionable mutations and tumor characteristics that can direct therapy. These biomarkers can be collected at higher frequencies than imaging or tissue sampling, potentially allowing for more informed management. This review will evaluate the roles of circulating biomarkers in breast cancer, including the serum markers Carcinoembryonic antigen CA15-3, CA27-29, HER2 ECD, and investigatory markers such as GP88; and the components of the liquid biopsy, including circulating tumor cells, cell free DNA/DNA methylation, circulating tumor DNA, and circulating microRNA.

Greatly Enhanced CTC Culture Enabled by Capturing CTC Heterogeneity Using a PEGylated PDMS-Titanium-Gold Electromicrofluidic Device with Glutathione-Controlled Gentle Cell Release.

The circulating tumor cells (CTCs, the root cause of cancer metastasis and poor cancer prognosis) are very difficult to culture for scale-up in vitro, which has hampered their use in cancer research/prognosis and patient-specific therapeutic development. Herein, we report a robust electromicrofluidic chip for not only efficient capture of heterogeneous (EpCAM+ and CD44+) CTCs with high purity but also glutathione-controlled gentle release of the CTCs with high efficiency and viability. This is enabled by coating the polydimethylsiloxane (PDMS) surface in the device with a 10 nm gold layer through a 4 nm titanium coupling layer, for convenient PEGylation and linkage of capture antibodies via the thiol-gold chemistry. Surprisingly, the percentage of EpCAM+ mammary CTCs can be as low as ∼35% (∼70% on average), showing that the commonly used approach of capturing CTCs with EpCAM alone may miss many EpCAM- CTCs. Furthermore, the CD44+ CTCs can be cultured to form 3D spheroids efficiently for scale-up. In contrast, the CTCs captured with EpCAM alone are poor in proliferation in vitro, consistent with the literature. By capture of the CTC heterogeneity, the percentage of stage IV patients whose CTCs can be successfully cultured/scaled up is improved from 12.5% to 68.8%. These findings demonstrate that the common practice of CTC capture with EpCAM alone misses the CTC heterogeneity including the critical CD44+ CTCs. This study may be valuable to the procurement and scale-up of heterogeneous CTCs, to facilitate the understanding of cancer metastasis and the development of cancer metastasis-targeted personalized cancer therapies conveniently via the minimally invasive liquid/blood biopsy.

Metformin Bicarbonate-Mediated Efficient RNAi for Precise Targeting of TP53 Deficiency in Colon and Rectal Cancers.

Colon and rectal cancers are the leading causes of cancer-related deaths in the United States and effective targeted therapies are in need for treating them. Our genomic analyses show hemizygous deletion of TP53, an important tumor suppressor gene, is highly frequent in both cancers, and the 5-year survival of patients with the more prevalent colon cancer is significantly reduced in the patients with the cancer harboring such deletion, although such reduction is not observed for rectal cancer. Unfortunately, direct targeting TP53 has been unsuccessful for cancer therapy. Interestingly, POLR2A, a gene essential for cell survival and proliferation, is almost always deleted together with TP53 in colon and rectal cancers. Therefore, RNA interference (RNAi) with small interfering RNAs (siRNAs) to precisely target/inhibit POLR2A may be an effective strategy for selectively killing cancer cells with TP53 deficiency. However, the difficulty of delivering siRNAs specifically into the cytosol where they perform their function, is a major barrier for siRNA-based therapies. Here, metformin bicarbonate (MetC) is synthesized to develop pH-responsive MetC-nanoparticles with a unique "bomb" for effective cytosolic delivery of POLR2A siRNA, which greatly facilitates its endo/lysosomal escape into the cytosol and augments its therapeutic efficacy of cancer harboring TP53 deficiency. Moreover, the MetC-based nanoparticles without functional siRNA show notable therapeutic effect with no evident toxicity or immunogenicity.

Patterns of Failure in Triple Negative Breast Cancer Patients in an Urban, Predominately Black Population.

Triple negative breast cancers (TNBC) behave more aggressively than hormone-receptor positive breast cancers. They are also known preferentially to affect young black women, often leading to poorer outcomes compared with those for white women. We sought to evaluate the comprehensive patterns of failure associated with treatment for TNBC at an urban institution with a predominantly black population and to assess the impact of social determinants of health on treatment failure. A retrospective review of TNBC patients treated from 2005 to 2015 was conducted. Detailed patient, tumor, and treatment characteristics and information on patterns of failure were included. With a median follow-up of 46 months, 32 (16%) documented failures occurred. Locoregional failures comprised 84% of failure patterns whether isolated or in combination with distant failure. Treatment failure was associated with insurance type and smoking status, as well as several tumor characteristics. On multivariate analysis, pathologic nodal staging was the most significant predictor of treatment failure. In contrast to previous studies, we found that black women had higher overall survival than white women, but race was not associated with differences in recurrence patterns or with likelihood of treatment failure. Regardless of race, of the patients who recurred, 53% failed in distant and locoregional sites simultaneously, with an additional 34% failing locally only. These results highlight the need for aggressive local therapies in high-risk patients and suggest a need for improved follow-up focusing on detecting locoregional failures. Multidisciplinary care is essential in the management of these patients at time of failure.

Anti-HER2 immunoliposomes for selective delivery of electron paramagnetic resonance imaging probes to HER2-overexpressing breast tumor cells.

Electron paramagnetic resonance (EPR) imaging is an emerging modality that can detect and localize paramagnetic molecular probes (so-called spin probes) in vivo. We previously demonstrated that nitroxide spin probes can be encapsulated in liposomes at concentrations exceeding 100 mM, at which nitroxides exhibit a concentration-dependent quenching of their EPR signal that is analogous to the self-quenching of fluorescent molecules. Therefore, intact liposomes encapsulating high concentrations of nitroxides exhibit greatly attenuated EPR spectral signals, and endocytosis of such liposomes represents a cell-activated contrast-generating mechanism. After endocytosis, the encapsulated nitroxide is liberated and becomes greatly diluted in the intracellular milieu. This dequenches the nitroxides to generate a robust intracellular EPR signal. It is therefore possible to deliver a high concentration of nitroxides to cells while minimizing background signal from unendocytosed liposomes. We report here that intracellular EPR signal can be selectively generated in a specific cell type by exploiting its expression of Human Epidermal Growth Factor Receptor 2 (HER2). When targeted by anti-HER2 immunoliposomes encapsulating quenched nitroxides, Hc7 cells, which are novel HER2-overexpressing cells derived from the MCF7 breast tumor cell line, endocytose the liposomes copiously, in contrast to the parent MCF7 cells or control CV1 cells, which do not express HER2. HER2-dependent liposomal delivery enables Hc7 cells to accumulate 750 µM nitroxide intracellularly. Through the use of phantom models, we verify that this concentration of nitroxides is more than sufficient for EPR imaging, thus laying the foundation for using EPR imaging to visualize HER2-overexpressing Hc7 tumors in animals.

Association of Serum Progranulin Levels With Disease Progression, Therapy Response and Survival in Patients With Metastatic Breast Cancer.

BACKGROUND: Progranulin (GP88) is a critical player in breast tumorigenesis. GP88 tumor expression is associated with increased recurrence and mortality, whereas GP88 circulating levels are elevated in patients with breast cancer compared with healthy individuals. We examined here the correlation between serum GP88 levels in patients with metastatic breast cancer (MBC) with overall survival and disease status determined as response to therapy or progression of disease. PATIENTS AND METHODS: An institutional review board (IRB)-approved study prospectively enrolled 101 patients with MBC at the University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center. GP88 serum levels were correlated with patients' disease status determined by Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria and survival outcomes by Kaplan-Meier analysis and log rank statistics. RESULTS: Patients' survival was stratified by serum GP88 level. Patients with serum GP88 < 55 ng/mL had a 4-fold increased survival compared with patients with GP88 > 55 ng/mL. Examination of GP88 serum levels in association with disease status showed a statistically significant association between serum GP88 levels and disease progression or response to therapy while CA15-3 level was only associated to progression. CONCLUSION: The association of serum GP88 level with survival and disease status suggests the potential of using the serum GP88 test for monitoring disease status in patients with MBC. Measurement of serum GP88 levels in patients with MBC may have clinical value as a cost-effective adjunct to the management of patients with MBC with imaging.