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Purpose: Stereotactic radiosurgery (SRS) is a highly effective therapy for newly diagnosed brain metastases. Prophylactic antiepileptic drugs are no longer routinely used in current SRS practice, owing to a perceived low overall frequency of new-onset seizures and potential side effects of medications. It is nonetheless desirable to prevent unwanted side effects following SRS. Risk factors for new-onset seizures after SRS have not been well established. As such, we aimed to characterize variables associated with increased seizure risk. Methods and Materials: Patients treated with SRS for newly diagnosed brain metastases between 2013 and 2016 were retrospectively reviewed at a single institution. Data on baseline demographics, radiation parameters, and clinical courses were collected. Results: The cohort consisted of 305 patients treated with SRS without prior seizure history. Median age and baseline Karnofsky Performance Scale score were 64 years (interquartile range, 55-70) and 80 (interquartile range, 80-90), respectively. Twenty-six (8.5%) patients developed new-onset seizures within 3 months of SRS. There was no association between new-onset seizures and median baseline Karnofsky Performance Scale score, prior resection, or prior whole brain radiation therapy. There were significant differences in the combined total irradiated volume (12.5 vs 3.7 cm3, P < .001), maximum single lesion volume (8.8 vs 2.8 cm3, P = .003), lesion diameter (3.2 vs 2.0 cm, P = .003), and number of lesions treated (3 vs 1, P = .018) between patients with and without new-onset seizures, respectively. On multivariate logistic regression, total irradiated volume (odds ratio, 1.09 for every 1-cm1 increase in total volume; confidence interval, 1.02-1.17; P = .016) and pre-SRS neurologic symptoms (odds ratio, 3.08; 95% confidence interval, 1.19-7.99; P = .020) were both significantly correlated with odds of seizures following SRS. Conclusions: Our data suggest that larger total treatment volume and the presence of focal neurologic deficits at presentation are associated with new-onset seizures within 3 months of SRS. High-risk patients undergoing SRS may benefit from counseling or prophylactic antiseizure therapy.

IntroductionTo assess the feasibility of a home-based aerobic exercise and nutrition counseling intervention and effect on cardiorespiratory fitness, cardiovascular disease risk profile, and immune response in obese endometrial cancer survivors.MethodsA longitudinal pilot study assessed a 12-week home-based aerobic exercise and nutrition counseling intervention in obese endometrial cancer survivors. The primary outcome was feasibility defined as 80% adherence to weekly walking sessions calculated among individuals that completed the intervention. Secondary outcomes comprised pre- and post-intervention differences in cardiorespiratory fitness, cardiovascular risk factors, and T-cell function. Descriptive statistics summarized data. Wilcoxon sign tests identified differences between and pre and post-intervention variables.ResultsNineteen women with stage 1 endometrial cancer consented; 9 withdrew and one was a screen failure. Median adherence to weekly walking sessions was 83.3%. Body composition was significantly altered with a reduction in median fat mass from 52.5 kg to 46.9 kg (p=0.04), and BMI from 37.5 kg/m2 to 36.2 kg/m2 (p = 0.004). There was no significant difference in cardiorespiratory fitness or cardiovascular parameters. The percentage of CD4+ and CD8+ T-cells producing IFNγ towards MAGE-A4 significantly increased from and 5.9% to 7.2% (p=0.043) and 13.9% to 14.8% (p=0.046), respectively. There were 3 related adverse events: hip pain, back sprain, and abdominal pain.DiscussionOur home-based exercise and nutrition counseling program was feasible based on 80% adherence to walking sessions and favored altered body composition. However, the discontinuation rate was high and further research is needed to overcome barriers to implementation. Improvement in cardiovascular parameters will most likely require longer and more intensive programs.

Abstract The interplay between the immune system and tumor progression is well recognized. However, current human breast cancer immunophenotyping studies are mostly focused on primary tumors with metastatic breast cancer lesions remaining largely understudied. To address this gap, we examined exome-capture RNA sequencing data from 50 primary breast tumors (PBTs) and their patient-matched metastatic tumors (METs) in brain, ovary, bone and gastrointestinal tract. We used gene expression signatures as surrogates for tumor infiltrating lymphocytes (TILs) and compared TIL patterns in PBTs and METs. Enrichment analysis and deconvolution methods both revealed that METs had a significantly lower abundance of total immune cells, including CD8+ T cells, regulatory T cells and dendritic cells. An exception was M2-like macrophages, which were significantly higher in METs across the organ sites examined. Multiplex immunohistochemistry results were consistent with data from the in-silico analysis and showed increased macrophages in METs. We confirmed the finding of a significant reduction in immune cells in brain METs (BRMs) by pathologic assessment of TILs in a set of 49 patient-matched pairs of PBT/BRMs. These findings indicate that METs have an overall lower infiltration of immune cells relative to their matched PBTs, possibly due to immune escape. RNAseq analysis suggests that the relative levels of M2-like macrophages are increased in METs, and their potential role in promoting breast cancer metastasis warrants further study.

Abstract Objective To investigate the predictive value of lymphovascular space invasion (LVSI) for nodal recurrence and overall survival (OS) in patients with stage I endometrioid endometrial cancer (EC) following surgical staging that included adequate lymph node sampling. Methods Retrospective analyses of patients undergoing surgical staging for FIGO stage I endometrioid EC between 1998 and 2015 were performed using an institutional database and the National Cancer Database (NCDB). Using the institutional database, logistic regression modeling identified predictors of nodal recurrence; Cox proportional hazards modeling was used to predict progression-free survival (PFS). Utilizing NCDB, Cox proportional hazards modeling was used to predict OS. The Kaplan-Meier method was used to estimate hazard ratios (HR). Survival curves were compared using the log-rank test. Results Among 275 institutional cases, LVSI was present in 48 (17.5%). There were 11 nodal recurrences: 18.8% (9/48) of cases with LVSI had a nodal recurrence compared to 0.88% (2/227) of those without LVSI. In multivariate analysis of institutional data, LVSI was the only significant predictor of nodal recurrence (p = 0.002). Among 28,076 NCDB cases, LVSI was present in 3766 (13.5%). In multivariate analysis of NCDB, grade 3, LVSI, and depth of invasion (all p

Summary: Notwithstanding the positive clinical impact of endocrine therapies in estrogen receptor-alpha (ERα)-positive breast cancer, de novo and acquired resistance limits the therapeutic lifespan of existing drugs. Taking the position that resistance is nearly inevitable, we undertook a study to identify and exploit targetable vulnerabilities that were manifest in endocrine therapy-resistant disease. Using cellular and mouse models of endocrine therapy-sensitive and endocrine therapy-resistant breast cancer, together with contemporary discovery platforms, we identified a targetable pathway that is composed of the transcription factors FOXA1 and GRHL2, a coregulated target gene, the membrane receptor LYPD3, and the LYPD3 ligand, AGR2. Inhibition of the activity of this pathway using blocking antibodies directed against LYPD3 or AGR2 inhibits the growth of endocrine therapy-resistant tumors in mice, providing the rationale for near-term clinical development of humanized antibodies directed against these proteins. : Cocce et al. show that FOXA1 contributes to disease pathogenesis by cooperating with GRHL2 in endocrine therapy-resistant breast cancer. LYPD3 is identified as an actionable downstream target of FOXA1/GRHL2, and humanized antibodies against LYDP3, or its ligand AGR2, demonstrate anti-tumor efficacy in animal models of endocrine therapy-resistant breast tumors. Keywords: FOXA1, tamoxifen, breast cancer, GRHL2, cistrome, enhancer, histone, chromatin, LYPD3

Background:. With growing concerns about the overuse of contralateral prophylactic mastectomy, optimizing unilateral mastectomy reconstruction outcomes becomes a priority. However, there remains a paucity of objective data that describe volumetric symmetry between a natural and autologous-reconstructed breast. Methods:. We evaluated patients who underwent unilateral mastectomy reconstruction with free-flap abdominal tissue transfer from 04/2006 to 01/2015, and had at least 2 postoperative magnetic resonance images (MRIs; n = 28). Using these MRI data, volumetric measurements of the reconstructed and natural breast were performed at the first postoperative MRI (after all revisions were complete) and the most recent MRI. Relationships were analyzed using Spearman correlation coefficients. A symmetry score (SS) was calculated such that values closer to 1.0 reflected volumetric symmetry. Results:. The mean age (years) and BMI of the patients was 44.8 and 26.8, respectively. The mean interval time between the MRIs was 3.03 years (range 0.43–6.6). After surgical revisions were complete, volumetric symmetry between reconstructed and nonreconstructed breasts was typically achieved (mean SS 0.92). This symmetry was also retained at the end of follow-up (mean SS 0.96), despite a mean change in BMI of 3.9% (range 1.1–7.7). Additionally, the mean number of flap revisions was 0.75 (range 0–2), and 39% of patients had a procedure performed on the natural breast. Conclusion:. In patients undergoing unilateral abdominal-based breast reconstruction, volumetric symmetry is attainable; however, it can require flap revisions and procedures to natural breast. Interestingly, this study does show that initial symmetry is retained postoperatively, regardless of changes in BMI.

IntroductionBreast cancer is a major cause of morbidity and mortality for women in Sub-Saharan Africa and for black American women. There is evidence that the pathologic characteristics of breast cancers in both African women and black American women may differ from their counterparts of European ancestry. However, despite the great burden of disease, data on pathologic features of breast carcinoma in Sub-Saharan Africa is limited and often contradictory. This lack of information makes it difficult to prioritize resource use in efforts to improve breast cancer outcomes in the region.MethodsWe examined consecutive cases of breast cancer in Tanzanian women (n = 83), black American women (n = 120), and white American women (n = 120). Each case was assessed for tumor type, grade, mitotic count, ER and HER2 status, and tumor infiltrating lymphocyte involvement.ResultsThe Tanzanian subjects were younger and had higher stage tumors than the subjects in either American group. Breast cancers in the Tanzanian and black American groups were more likely to be high grade (p = 0.008), to have a high mitotic rate (p

The objective of this study is to evaluate the association between tumor grade and response to chemotherapy in patients with endometrioid endometrial adenocarcinoma. Patients with advanced or recurrent endometrioid endometrial adenocarcinoma of known tumor grade who received at least 3 cycles of chemotherapy were retrospectively identified at three institutions. RECIST 1.1 criteria were used to assess response to neoadjuvant, postoperative or salvage chemotherapy. Chi-square testing was used to evaluate the association between tumor grade and chemotherapy response. Ninety-one patients met inclusion criteria: 13 with grade 1, 29 with grade 2 and 49 with grade 3 tumors. Eighty-four percent of patients received chemotherapy for recurrence, 12% for postoperative residual disease, and 4% in the neoadjuvant setting. The majority (85%) received carboplatin and paclitaxel. Forty-six percent (6/13) of grade 1, 72% (21/29) of grade 2 and 43% (21/49) of grade 3 tumors achieved an objective response. Grade 2 tumors were more likely to respond to chemotherapy compared to grade 3 tumors (72% vs. 43%, p = 0.02; Table 2), and specifically more likely to respond to carboplatin/paclitaxel (72% vs. 41%, p = 0.016). Median progression-free survival for patients receiving chemotherapy for recurrence or progression was 9 months for grade 1, 8 months for grade 2, and 5 months for grade 3 tumors. Similar results between grade and treatment response were apparent in the subset of 37 patients with a recently re-assigned tumor grade (G2 88% vs. G3 44%, p = 0.032). In this series of endometrioid endometrial cancers, grade 2 tumors had the best measurable response to chemotherapy.

Objective: The Lumbee Indian tribe is the largest Native American tribe in North Carolina, with about 55,000 enrolled members who mostly reside in southeastern counties. We evaluated whether Lumbee heritage is associated with high-risk histologic subtypes of endometrial cancer. Methods: We retrospectively analyzed the available records from IRB-approved endometrial cancer databases at two institutions of patients of Lumbee descent (year of diagnosis range 1980–2014). Each Lumbee case was matched by age, year of diagnosis, and BMI to two non-Lumbee controls. Chi-square test was used to compare categorical associations. Kaplan–Meier methods and log-rank test were used to display and compare disease-free survival (DFS) and overall survival (OS). Multivariate Cox proportional hazards regression was used to adjust for age and BMI while testing cohort as a predictor of DFS and OS. Results: Among 108 subjects, 10/35 (29%) Lumbee and 19/72 (26%) non-Lumbee subjects had high-risk (serous/clear cell/carcinosarcoma) histologic types (p = 0.8). 12/35 (34%) Lumbee and 24/72 (33%) non-Lumbee subjects had grade 3 tumors (p = 0.9). 5/33 (15%) Lumbee and 13/72 (18%) non-Lumbee had advanced stage endometrial cancer at diagnosis (p = 0.7). Lumbee ancestry was not associated with worse survival outcomes. OS (p = 0.054) and DFS (p = 0.01) were both worse in Blacks compared to Lumbee and White subjects. Conclusion: In this retrospective cohort analysis, Lumbee Native American ancestry was not a significant independent predictor of rates of high-risk histological subtypes of endometrial cancer or poor survival outcomes.

Objective: To determine the rate and performance of sentinel lymph node (SLN) mapping among women with high-risk endometrial cancers. Methods: Patients diagnosed between 2012 and 2015 with uterine cancer of grade 3 endometrioid, clear cell, serous or carcinosarcoma histology and who underwent SLN mapping prior to full pelvic lymph node dissection were included. Subjects underwent methylene blue or ICG injection for laparoscopic (N = 16) or robotic-assisted laparoscopic (N = 20) staging. Outcomes included SLN mapping rates, SLN and non-SLN positive rates, false negative SLN algorithm rate, and the negative predictive value (NPV) of the SLN algorithm. Fisher's exact test was used to compare mapping and node positivity rates. Results: 9/36 (25%) patients with high-risk uterine cancer had at least one metastatic lymph node identified. Successful mapping occurred in 30/36 (83%) patients. SLN mapped to pelvic nodes bilaterally in 20 (56%), unilaterally in 9 (25%), and aortic nodes only in 1 (3%). Malignancy was identified in 14/95 (15%) of all sentinel nodes and 12/775 (1.5%) of all non-sentinel nodes (p

Expression of human epidermal growth factor family member 3 (HER3), a critical heterodimerization partner with EGFR and HER2, promotes more aggressive biology in breast and other epithelial malignancies. As such, inhibiting HER3 could have broad applicability to the treatment of EGFR- and HER2-driven tumors. Although lack of a functional kinase domain limits the use of receptor tyrosine kinase inhibitors, HER3 contains antigenic targets for T cells and antibodies. Using novel human HER3 transgenic mouse models of breast cancer, we demonstrate that immunization with recombinant adenoviral vectors encoding full length human HER3 (Ad-HER3-FL) induces HER3-specific T cells and antibodies, alters the T cell infiltrate in tumors, and influences responses to immune checkpoint inhibitions. Both preventative and therapeutic Ad-HER3-FL immunization delayed tumor growth but were associated with both intratumoral PD-1 expressing CD8+ T cells and regulatory CD4+ T cell infiltrates. Immune checkpoint inhibition with either anti-PD-1 or anti-PD-L1 antibodies increased intratumoral CD8+ T cell infiltration and eliminated tumor following preventive vaccination with Ad-HER3-FL vaccine. The combination of dual PD-1/PD-L1 and CTLA4 blockade slowed the growth of tumor in response to Ad-HER3-FL in the therapeutic model. We conclude that HER3-targeting vaccines activate HER3-specific T cells and induce anti-HER3 specific antibodies, which alters the intratumoral T cell infiltrate and responses to immune checkpoint inhibition.

Gretchen Kimmick1,2, Gloria Broadwater2, Mara Vitolins31Medical Oncology, Wake Forest University School of Medicine, Winston-Salem; 2Cancer Center Biostatistics, Duke University Medical Center, Durham; 3Department of Epidemiology and Prevention, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USAAims: In breast cancer survivors, we aimed to describe the frequency of hot flashes and night sweats, frequency and type of treatment, and the association of hot flashes and use of calcium supplements.Methods: Charts of breast cancer survivors were reviewed for information about hot flashes, treatment for hot flashes, and calcium supplementation. Associations between variables were explored using the Chi-square test and Fisher’s Exact test.Results: Eighty-six charts were reviewed. Mean age of the women was 58 years and 79% were postmenopausal. Forty-two (49%) of women had hot flashes and 18 (21%) had night sweats. Thirty-one (36%) were treated for hot flashes. Treatment included selective serotonin reuptake inhibitors/serotonin-norepinephrine reuptake inhibitors (n = 19), clonidine (n = 7), Bellergal-S® (n = 8), sleep-aid (n = 7), and other (n = 5). Calcium supplementation was recorded in 31%. Of women with hot flashes, 44% took calcium supplements; of women without hot flashes, 18% took calcium supplements (Chi-square P = 0.02).Conclusion: Hot flashes were recorded in 49% of this group of primarily postmenopausal breast cancer survivors. Women with hot flashes were more likely to be taking calcium ­supplements. Further exploration of the association between hot flashes and calcium supplementation is warranted.Keywords: hot flashes, breast cancer, calcium supplementation

To define the biology driving the aggressive nature of breast cancer arising in young women.Among 784 patients with early stage breast cancer, using prospectively-defined, age-specific cohorts (young or=65 years), 411 eligible patients (n = 200or=65 years) with clinically-annotated Affymetrix microarray data were identified. GSEA, signatures of oncogenic pathway deregulation and predictors of chemotherapy sensitivity were evaluated within the two age-defined cohorts.In comparing deregulation of oncogenic pathways between age groups, a higher probability of PI3K (p = 0.006) and Myc (p = 0.03) pathway deregulation was observed in breast tumors arising in younger women. When evaluating unique patterns of pathway deregulation, a low probability of Src and E2F deregulation in tumors of younger women, concurrent with a higher probability of PI3K, Myc, and beta-catenin, conferred a worse prognosis (HR = 4.15). In contrast, a higher probability of Src and E2F pathway activation in tumors of older women, with concurrent low probability of PI3K, Myc and beta-catenin deregulation, was associated with poorer outcome (HR = 2.7). In multivariate analyses, genomic clusters of pathway deregulation illustrate prognostic value.Results demonstrate that breast cancer arising in young women represents a distinct biologic entity characterized by unique patterns of deregulated signaling pathways that are prognostic, independent of currently available clinico-pathologic variables. These results should enable refinement of targeted treatment strategies in this clinically challenging situation.