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Patrick M Dillon,1 Christiana M Brenin,1 Craig L Slingluff Jr2 1University of Virginia, Division of Hematology/Oncology, Charlottesville, VA 22908, USA; 2University of Virginia, Department of Surgery, Charlottesville, VA 22908, USACorrespondence: Patrick M DillonDivision of Hematology/Oncology, University of Virginia, Box 800716, Charlottesville, VA 22908, USATel +1-434-982-1495Fax +1-434-244-7534Email Pmd5b@hscmail.mcc.virginia.eduAbstract: Vaccine therapies for treatment and prevention of cancer have seen modest degrees of efficacy with wide variation related to the tumor type, vaccine type, adjuvants and clinical setting for their study. Over the course of the last two decades, various peptide vaccines for breast cancer have been studied. The current leading peptide vaccine for human application is a HER2-based vaccine known as Nelipepimut-S, which has demonstrated immune activity and promising clinical activity in some settings. This review covers the development of this newer peptide vaccine for both HER2 amplified and non-amplified breast cancer.Keywords: vaccine, breast cancer, HER2, peptide, human

The purpose of this study was multifaceted: to initiate an interdisciplinary collaborative relationship between nursing and medical students; to determine the usefulness of an interdisciplinary approach using simulations as an educational strategy; and to analyze students' perceptions of collaboration. A pre/posttest design was used to assess students' perceptions of interdisciplinary collaboration with a mock code experience using a high-fidelity simulator. Open-ended questions provided another perspective of interdisciplinary collaboration. A convenience sample of fourth-year nursing students and third-year medical students from a large urban university participated in the study. Statistically significant differences (p < 0.05) were seen in medical students' posttest scores for two factors, collaboration and nursing autonomy. The narrative responses revealed that nursing students' perceptions of the nurse-physician relationship became more collaborative after the simulation experience. Both medical and nursing students described the experience as one that should be continued. [ABSTRACT FROM AUTHOR]

Combination therapy is increasingly being explored as a promising approach for improving cancer treatment outcomes. However, identifying effective dose combinations in early oncology drug development is challenging due to limited sample sizes in early-phase clinical trials. This task becomes even more complex when multiple agents are being escalated simultaneously, potentially leading to a loss of monotonic toxicity order with respect to the dose. Traditional single-agent trial designs are insufficient for this multi-dimensional problem, necessitating the development and implementation of dose-finding methods specifically designed for drug combinations. While, in practice, approaches to this problem have focused on preselecting combinations with a known toxicity order and applying single-agent designs, this limits the number of combinations considered and may miss promising dose combinations. In recent years, several novel designs have been proposed for exploring partially ordered drug combination spaces with the goal of identifying a maximum tolerated dose combination, based on safety, or an optimal dose combination, based on toxicity and efficacy. However, their implementation in clinical practice remains limited. In this article, we describe the application of the partial order continual reassessment method and its extensions for combination therapies in early-phase clinical trials. We present completed trials that use safety endpoints to identify maximum tolerated dose combinations and adaptively use both safety and efficacy endpoints to determine optimal treatment strategies. We discuss the effectiveness of the partial-order continual reassessment method and its extensions in identifying optimal treatment strategies and provide our experience with executing these novel adaptive designs in practice. By utilizing innovative dose-finding methods, researchers and clinicians can more effectively navigate the challenges of combination therapy development, ultimately improving patient outcomes in the treatment of cancer., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

In the past decade, defective DNA repair has been increasingly linked with cancer progression. Human tumors with markers of defective DNA repair and increased replication stress exhibit genomic instability and poor survival rates across tumor types. Seminal studies have demonstrated that genomic instability develops following inactivation of BRCA1, BRCA2, or BRCA-related genes. However, it is recognized that many tumors exhibit genomic instability but lack BRCA inactivation. We sought to identify a pan-cancer mechanism that underpins genomic instability and cancer progression in BRCA-wildtype tumors. Methods: Using multi-omics data from two independent consortia, we analyzed data from dozens of tumor types to identify patient cohorts characterized by poor outcomes, genomic instability, and wildtype BRCA genes. We developed several novel metrics to identify the genetic underpinnings of genomic instability in tumors with wildtype BRCA. Associated clinical data was mined to analyze patient responses to standard of care therapies and potential differences in metastatic dissemination. Results: Systematic analysis of the DNA repair landscape revealed that defective single-strand break repair, translesion synthesis, and non-homologous end-joining effectors drive genomic instability in tumors with wildtype BRCA and BRCA-related genes. Importantly, we find that loss of these effectors promotes replication stress, therapy resistance, and increased primary carcinoma to brain metastasis. Conclusions: Our results have defined a new pan-cancer class of tumors characterized by replicative instability (RIN). RIN is defined by the accumulation of intra-chromosomal, gene-level gain and loss events at replication stress sensitive (RSS) genome sites. We find that RIN accelerates cancer progression by driving copy number alterations and transcriptional program rewiring that promote tumor evolution. Clinically, we find that RIN drives therapy resistance and distant metastases across multiple tumor types.

Purpose: Patients with pretreated estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer have poor prognosis. Elacestrant is a novel, oral selective ER degrader that demonstrated activity in early studies., Methods: This randomized, open-label, phase III trial enrolled patients with ER-positive/HER2-negative advanced breast cancer who had one-two lines of endocrine therapy, required pretreatment with a cyclin-dependent kinase 4/6 inhibitor, and ≤ 1 chemotherapy. Patients were randomly assigned to elacestrant 400 mg orally once daily or standard-of-care (SOC) endocrine monotherapy. Primary end points were progression-free survival (PFS) by blinded independent central review in all patients and patients with detectable ESR1 mutations., Results: Patients were randomly assigned to elacestrant (n = 239) or SOC (n = 238). ESR1 mutation was detected in 47.8% of patients, and 43.4% received two prior endocrine therapies. PFS was prolonged in all patients (hazard ratio = 0.70; 95% CI, 0.55 to 0.88; P = .002) and patients with ESR1 mutation (hazard ratio = 0.55; 95% CI, 0.39 to 0.77; P = .0005). Treatment-related grade 3/4 adverse events occurred in 7.2% receiving elacestrant and 3.1% receiving SOC. Treatment-related adverse events leading to treatment discontinuations were 3.4% in the elacestrant arm versus 0.9% in SOC. Nausea of any grade occurred in 35.0% receiving elacestrant and 18.8% receiving SOC (grade 3/4, 2.5% and 0.9%, respectively)., Conclusion: Elacestrant is the first oral selective ER degrader demonstrating a significant PFS improvement versus SOC both in the overall population and in patients with ESR1 mutations with manageable safety in a phase III trial for patients with ER-positive/HER2-negative advanced breast cancer.

Introduction: There are more than two dozen bispecific antibodies (BsAbs) in development with a variety of designs which are relevant to breast cancer. The field of BsAbs for breast cancer includes agents that co-direct immune recognition of the cancer cell, target unique cancer antigens, and target the microenvironment. BsAbs are being developed for use as antibody-drug conjugates and as homing signals for engineered T-cells., Areas Covered: This review covers potential targets for bispecific antibodies, agents in pre-clinical development, agents in clinical trials, combinatorial therapies, and future directions., Expert Opinion: There is no BsAb approval expected for breast cancer in the near term, but late-stage trials are underway. Future BsAb roles in breast cancer are possible given unmet needs in estrogen receptor+ disease, residual disease, and de-escalating chemotherapy use. The HER2+ space shows hints of success for BsAbs, but is already crowded. Areas of unmet need still exist.

Background: Public health concern over college students mixing caffeine-containing energy drinks (EDs) and alcohol has contributed to an array of ED-focused research studies. One review found consistent associations between ED use and heavy/problem drinking as well as other drug use and risky behaviors (Nutr Rev 72:87-97, 2014). The extent to which similar patterns exist for other sources of caffeine is not known. The present study examined associations between coffee and ED consumption and alcohol, tobacco and other drug use; alcohol use problems; and parental substance abuse and mental health problems in a sample of college freshmen., Methods: Subjects were N = 1986 freshmen at an urban university who completed an on-line survey about demographics; caffeine; alcohol, tobacco and other drug use; and family history. The sample was 61% female and 53% White. Chi-square analyses and multivariable binary or ordinal logistic regression were used to compare substance use, problem alcohol behavior, and familial risk measures across 3 caffeine use groups: ED (with or without Coffee) (ED + Co; N = 350); Coffee but no ED (Co; N = 761); and neither coffee nor ED (NoCE; N = 875) use., Results: After adjusting for gender and race, the 3 caffeine use groups differed on 8 of 9 symptoms for alcohol dependence. In all cases, the ED + Co group was most likely to endorse the symptom, followed by the Co group and finally the NoCE group (all p < .002). A similar pattern was found for: use 6+ times of 5 other classes of drugs (all p < .05); extent of personal and peer smoking (all p < .001); and paternal problems with alcohol, drugs and anxiety/depression as well as maternal alcohol problems and depression/anxiety (p < .04)., Conclusions: The response pattern was ubiquitous, with ED + Co most likely, Co intermediate, and NoCE least likely to endorse a broad range of substance use, problem alcohol behaviors, and familial risk factors. The finding that the Co group differed from both the ED + Co and NoCE groups on 8 measures and from the NoCE group on one additional measure underscores the importance of looking at coffee in addition to EDs when considering associations between caffeine and other risky behaviors., (© 2022. The Author(s).)

Chemotherapy has been used to inhibit cancer growth for decades, but emerging evidence shows it can affect the tumor stroma, unintentionally promoting cancer malignancy. After treatment of primary tumors, remaining drugs drain via lymphatics. Though all drugs interact with the lymphatics, we know little of their impact on them. Here, we show a previously unknown effect of platinums, a widely used class of chemotherapeutics, to directly induce systemic lymphangiogenesis and activation. These changes are dose-dependent, long-lasting, and occur in healthy and cancerous tissue in multiple mouse models of breast cancer. We found similar effects in human ovarian and breast cancer patients whose treatment regimens included platinums. Carboplatin treatment of healthy mice prior to mammary tumor inoculation increased cancer metastasis as compared to no pre-treatment. These platinum-induced phenomena could be blocked by VEGFR3 inhibition. These findings have implications for cancer patients receiving platinums and may support the inclusion of anti-VEGFR3 therapy into treatment regimens or differential design of treatment regimens to alter these potential effects., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Harris, Esparza, Azimi, Cornelison, Azar, Llaneza, Belanger, Mathew, Tkachenko, Perez, Rosean, Bostic, Cornelison, Tate, Peirce-Cottler, Paquette, Mills, Landen, Saucerman, Dillon, Pompano, Rutkowski and Munson.)

Purpose: High-value and high-quality health care requires outcome measurements to inform treatment decisions, but, to our knowledge, no standardized measurements exist to evaluate brain metastases (BMs) care. We propose a set of measurements and report on their implementation in the care of patients with BMs., Methods: On the basis of a stakeholders' needs assessment and review of the literature, we identified outcome and process measurements to assess the care of patients with BMs according to treatment modality. Retrospectively, we applied these indicators of care to all patients diagnosed and treated at our institution over 2 years., Results: We ascertained 5 outcome and 6 process measurements of relevance in the care of BMs. When applied to 209 patients (89.7%) who received cancer treatment, 77% were alive > 90 days after diagnosis. The proportion alive at 90 days after surgery, whole-brain radiation therapy (WBRT), and stereotactic radiosurgery (SRS) was 82%, 59%, and 81%, respectively. Other performance measurements included 30-day postoperative readmission rate (6%), SRS within 30 days of surgery (79%), use of memantine with WBRT (41%), advance directives within 6 months of diagnosis (53%), and palliative care consultation for patients with poor prognosis or receiving WBRT (45%). Measurements for the 24 patients (10.3%) receiving best supportive care were advance directives documentation (67%) and referral to palliative or hospice care (83%)., Conclusion: We propose a set of measurements to apprise quality improvement efforts, inform treatment decision-making, and to use in evaluation of the performance of interdisciplinary BMs programs. Their refinement can potentially enhance the quality and value of care delivered to patients with BMs.

This paper describes the design of an early phase, prospective trial evaluating the safety and tolerability of the combination of the histone deacetylase inhibitor, entinostat, in combination with capecitabine. The study consists of two parts; an initial phase evaluating the safety of the combination in participants with metastatic breast cancer, followed by a second phase assessing the safety of the combination in participants with residual disease after neo-adjuvant chemotherapy for breast cancer. We describe the adaptation of a model-based design for identifying the maximum tolerated dose combination that efficiently moves from the initial phase in an advanced disease population to the second phase in the target population. Operating characteristics demonstrate the ability of the method to accurately predict true maximum tolerated dose combinations in a high percentage of trials with reasonable sample sizes, while treating participants at and around desirable combinations. The proposed design is a practical, early-phase, adaptive method for use with drug combination dose finding in the presence of shifting patient populations. More challenging research questions are being investigated in early-phase trials, which has created the need to implement more flexible designs that can meet the objectives of current studies, such as those exploring drug combinations while addressing patient heterogeneity. Our goal is to facilitate acceptance and application of more novel designs in contemporary early-phase studies., Competing Interests: The authors declare no potential conflicts of interest., (© 2020 The Authors.)

The immune inhibitory enzyme indoleamine 2,3-dioxygenase (IDO) has been associated with immune evasion in numerous malignancies and may mark these cancers as susceptible to anti-IDO therapies. We herein address IDO expression in breast cancers, examine the relationship between IDO and PD-L1, and investigate IDO fidelity across breast cancer primaries and metastases. IDO and PD-L1 expression was assessed in tissue microarrays containing 242 invasive primary breast cancers, 20 nodal metastases, and 19 distant metastases. IDO and PD-L1 were scored by extent in the tumor cells and immune infiltrate. Tumor IDO staining was seen in 14% of primaries including 38% of triple-negative cancers. IDO immune cell staining was seen in 14% of primaries and 29% of triple-negative cancers. Tumoral IDO and PD-L1 co-expression was seen in 8% of primaries, including 70% of tumoral PD-L1-positive cases. Immune IDO and PD-L1 co-expression was identified in 14% of primaries, including 48% of immune PD-L1-positive cases. Tumoral and immune cell IDO was conserved in 94% of matched primary/metastasis. In summary, IDO expression is common among high-grade, triple-negative breast cancers and is frequently associated with PD-L1 co-expression, suggesting that IDO might be a mechanism of anti-PD-1/PD-L1 immunotherapy resistance and that dual therapy may be of utility. Tumoral and immune cell IDO expression shows fidelity between primary and metastatic sites in treatment-naïve cancers, arguing against IDO as an independent driver for metastatic spread. Clinical trials are needed to assess the efficacy of IDO inhibition relative to IDO expression, as well as its possible role in combination with anti-PD-1/PD-L1 immunotherapy.

Mismatch repair (MMR) deficiency in solid tumors has recently been linked to susceptibility to immunotherapies targeting the programmed cell death-1 (PD-1)/programmed cell death-1 ligand (PD-L1) axis. Loss of MMR proteins has been shown to correlate with tumoral PD-L1 expression in colorectal and endometrial carcinomas, but the association between expression of MMR proteins and PD-L1 has not previously been studied in breast carcinoma, where MMR deficiency is less common. We assessed the relationship between PD-L1 and MMR protein expression by immunohistochemistry in 245 primary and 40 metastatic breast carcinomas. Tumoral staining for PD-L1 was positive in 12% of all cases, including 32% of triple-negative cancers. MMR deficiency was observed in 0.04% of breast cancers; the single MMR-deficient case was a high-grade, triple-negative ductal carcinoma which showed dual loss of MLH1 and PMS2 proteins and expressed PD-L1. Two ER carcinomas initially were scored with MMR protein loss in tissue microarray format but were subsequently shown to be MMR-intact on whole sections. Analysis of MMR gene mutation in The Cancer Genome Atlas corroborates low frequency of MMR deficiency for invasive breast cancer. MMR protein expression is therefore unlikely to show utility as a screen for immunotherapeutic vulnerability in this tumor type, and may provoke unwarranted genetic testing in patients unlikely to have a heritable cancer syndrome. PD-L1 may be a more clinically relevant biomarker for anti-PD-1/PD-L1 therapies in this setting.

Background: For more than a decade, a large proportion of research on caffeine use in college students has focused on energy drinks (ED), demonstrating an association between ED consumption and heavy/problem alcohol use. The present study examined the relationship between daily coffee consumption and varied measures of alcohol use and problems in a sample of college women., Methods: Participants were undergraduate females (N=360) attending an urban university in 2001-02 and prior to the rise in ED popularity on college campuses. Analyses compared women who reported drinking coffee daily (DC; 16.9%), to women who did not (NDC; 83.1%) on standardized measures of alcohol use and problems., Results: For both past month and year of drinking, DC women generally reported consuming more alcohol and were 2.1-2.6 times more likely to screen at risk for alcohol problems than their NDC counterparts. DC women were also more likely than NDC women to report problems related to drinking (e.g., experiencing blackouts, inability to stop drinking after they had started)., Conclusions: Findings support potential benefits of health education and screening that goes beyond EDs, focusing on varied forms of caffeine consumption., Competing Interests: Disclosure of interest: The authors report no conflicts of interest.

Many cancer therapeutic agents have shown to be effective for treating multiple cancer types. Yet major challenges exist toward introducing a novel drug used in one cancer type to different cancer types, especially when a relatively small number of patients with the other cancer type often benefit from anti-cancer therapy with the drug. Recently, many novel agents were introduced to different cancer types together with companion biomarkers which were obtained or biologically assumed from the original cancer type. However, there is no guarantee that biomarkers from one cancer can directly predict a therapeutic response in another. To tackle this challenging question, we have developed a concordant expression biomarker-based technique ("CONCORD") that overcomes these limitations. CONCORD predicts drug responses from one cancer type to another by identifying concordantly co-expressed biomarkers across different cancer systems. Application of CONCORD to three standard chemotherapeutic agents and two targeted agents demonstrated its ability to accurately predict the effectiveness of a drug against new cancer types and predict therapeutic response in patients., Competing Interests: CONFLICTS OF INTEREST None of the authors have competing interests.

Background: Breast cancer remains a leading cause of cancer death worldwide. There is evidence that immunotherapy may play a role in the eradication of residual disease. Peptide vaccines for immunotherapy are capable of durable immune memory, but vaccines alone have shown sparse clinical activity against breast cancer to date. Toll-like receptor (TLR) agonists and helper peptides are excellent adjuvants for vaccine immunotherapy and they are examined in this human clinical trial., Methods: A vaccine consisting of 9 MHC class I-restricted breast cancer-associated peptides (from MAGE-A1, -A3, and -A10, CEA, NY-ESO-1, and HER2 proteins) was combined with a TLR3 agonist, poly-ICLC, along with a helper peptide derived from tetanus toxoid. The vaccine was administered on days 1, 8, 15, 36, 57, 78. CD8 + T cell responses to the vaccine were assessed by both direct and stimulated interferon gamma ELIspot assays., Results: Twelve patients with breast cancer were treated: five had estrogen receptor positive disease and five were HER2 amplified. There were no dose-limiting toxicities. Toxicities were limited to Grade 1 and Grade 2 and included mild injection site reactions and flu-like symptoms, which occurred in most patients. The most common toxicities were injection site reaction/induration and fatigue, which were experienced by 100% and 92% of participants, respectively. In the stimulated ELIspot assays, peptide-specific CD8 + T cell responses were detected in 4 of 11 evaluable patients. Two patients had borderline immune responses to the vaccine. The two peptides derived from CEA were immunogenic. No difference in immune response was evident between patients receiving endocrine therapy and those not receiving endocrine therapy during the vaccine series., Conclusions: Peptide vaccine administered in the adjuvant breast cancer setting was safe and feasible. The TLR3 adjuvant, poly-ICLC, plus helper peptide mixture provided modest immune stimulation. Further optimization is required for this multi-peptide vaccine/adjuvant combination., Trial Registration: ClinicalTrials.gov (posted 2/15/2012): NCT01532960. Registered 2/8/2012. https://clinicaltrials.gov/show/NCT01532960.

Importance: We previously reported that survival is poorer from histopathologically amelanotic than pigmented melanoma because of more advanced stage at diagnosis. Identifying patients at risk of amelanotic melanoma might enable earlier diagnosis and improved survival; however, the phenotypic characteristics and underlying genetics associated with amelanotic melanoma are unknown., Objective: To determine whether phenotypic characteristics, carriage of MC1R variants, and history of amelanotic melanoma are associated with histopathologically amelanotic melanoma., Design, Setting, and Participants: The Genes, Environment, and Melanoma (GEM) study is an international cohort study that enrolled patients with incident primary cutaneous melanomas from population-based and hospital-based cancer registries (1998 to 2003). The GEM participants included here were 2387 patients with data for phenotypes, MC1R genotype, and primary melanomas scored for histopathologic pigmentation. Of these 2387 patients with incident melanomas scored for pigmentation, 527 had prior primary melanomas also scored for pigmentation., Main Outcomes and Measures: Associations of phenotypic characteristics (freckles, nevi, phenotypic index) and MC1R status with incident amelanotic melanomas were evaluated using logistic regression models adjusted for age, sex, study center, and primary status (single or multiple primary melanoma); odds ratios (ORs) and 95% CIs are reported. Association of histopathologic pigmentation between incident and prior melanomas was analyzed using an exact logistic regression model., Results: This study included 2387 patients (1065 women, 1322 men; mean [SD] age at diagnosis, 58.3 [16.1] years) and 2917 primary melanomas. In a multivariable model including phenotypic characteristics, absence of back nevi, presence of many freckles, and a sun-sensitive phenotypic index were independently associated with amelanotic melanoma. Carriage of MC1R variants was associated with amelanotic melanoma but lost statistical significance in a model with phenotype. Further, patients with incident primary amelanotic melanomas were more likely to have had a prior primary amelanotic melanoma (OR, 4.62; 95% CI, 1.25-14.13) than those with incident primary pigmented melanomas., Conclusions and Relevance: Absence of back nevi, presence of many freckles, a sun-sensitive phenotypic index, and prior amelanotic melanoma increase odds for development of amelanotic melanoma. An increased index of suspicion for melanoma in presenting nonpigmented lesions and more careful examination for signs of amelanotic melanoma during periodic skin examination in patients at increased odds of amelanotic melanoma might lead to earlier diagnosis and improved survival.

Purpose: Genetic and preclinical studies have implicated FGFR signaling in the pathogenesis of adenoid cystic carcinoma (ACC). Dovitinib, a suppressor of FGFR activity, may be active in ACC. Experimental Design: In a two-stage phase II study, 35 patients with progressive ACC were treated with dovitinib 500 mg orally for 5 of 7 days continuously. The primary endpoints were objective response rate and change in tumor growth rate. Progression-free survival, overall survival, metabolic response, biomarker, and quality of life were secondary endpoints. Results: Of 34 evaluable patients, 2 (6%) had a partial response and 22 (65%) had stable disease >4 months. Median PFS was 8.2 months and OS was 20.6 months. The slope of the overall TGR fell from 1.95 to 0.63 on treatment ( P < 0.001). Toxicity was moderate; 63% of patients developed grade 3-4 toxicity, 94% required dose modifications, and 21% stopped treatment early. An early metabolic response based on 18 FDG-PET scans was seen in 3 of 15 patients but did not correlate with RECIST response. MYB gene translocation was observed and significantly correlated with overexpression of MYB but did not correlate with FGFR1 phosphorylation or clinical response to dovitinib. Conclusions: Dovitinib produced few objective responses in patients with ACC but did suppress the TGR with a PFS that compares favorably with those reported with other targeted agents. Future studies of more potent and selective FGFR inhibitors in biomarker-selected patients will be required to determine whether FGFR signaling is a valid therapeutic target in ACC. Clin Cancer Res; 23(15); 4138-45. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Purpose: Because of inherent disease heterogeneity, targeted therapies have eluded triple-negative breast cancer (TNBC), and biomarkers predictive of treatment response have not yet been identified. This study was designed to determine whether the mTOR inhibitor everolimus with cisplatin and paclitaxel would provide synergistic antitumor effects in TNBC. Methods: Patients with stage II/III TNBC were enrolled in a randomized phase II trial of preoperative weekly cisplatin, paclitaxel and daily everolimus or placebo for 12 weeks, until definitive surgery. Tumor specimens were obtained at baseline, cycle 1, and surgery. Primary endpoint was pathologic complete response (pCR); secondary endpoints included clinical responses, breast conservation rate, safety, and discovery of molecular features associated with outcome. Results: Between 2009 and 2013, 145 patients were accrued; 36% of patients in the everolimus arm and 49% of patients in the placebo arm achieved pCR; in each arm, 50% of patients achieved complete responses by imaging. Higher rates of neutropenia, mucositis, and transaminase elevation were seen with everolimus. Clinical response to therapy and long-term outcome correlated with increased frequency of DNA damage response (DDR) gene mutations, Basal-like1 and Mesenchymal TNBC-subtypes, AR-negative status, and high Ki67, but not with tumor-infiltrating lymphocytes. Conclusions: The paclitaxel/cisplatin combination was well tolerated and active, but addition of everolimus was associated with more adverse events without improvement in pCR or clinical response. However, discoveries made from correlative studies could lead to predictive TNBC biomarkers that may impact clinical decision-making and provide new avenues for mechanistic exploration that could lead to clinical utility. Clin Cancer Res; 23(15); 4035-45. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Background: Early palliative care for advanced cancer patients improves quality of life and survival, but less is known about its effect on intensive care unit (ICU) use at the end of life. This analysis assessed the effect of a comprehensive early palliative care program on ICU use and other outcomes among patients with advanced cancer., Patients and Methods: A retrospective cohort of patients with advanced cancer enrolled in an early palliative care program ( n  = 275) was compared with a concurrent control group of patients receiving standard care ( n  = 195) during the same time period by using multivariable logistic regression analysis. The multidisciplinary outpatient palliative care program used early end-of-life care planning, weekly interdisciplinary meetings to discuss patient status, and patient-reported outcomes assessment integrated within the electronic health record., Results: Patients in the control group had statistically significantly higher likelihood of ICU admission at the end of life (odds ratios [ORs]: last 6 months, 3.07; last month, 3.59; terminal admission, 4.69), higher likelihood of death in the hospital (OR, 4.14) or ICU (OR, 5.57), and lower likelihood of hospice enrollment (OR, 0.13). Use of chemotherapy or radiation did not significantly differ between groups, nor did length of ICU stay, code status, ICU procedures (other than cardiopulmonary resuscitation), disposition location, and outcomes after ICU admission., Conclusion: Early palliative care significantly reduced ICU use at the end of life but did not change ICU events. This study supports early initiation of palliative care for advanced cancer patients before hospitalizations and intensive care. The Oncologist 2017;22:318-323 IMPLICATIONS FOR PRACTICE: Palliative care has shown clear benefit in quality of life and survival in advanced cancer patients, but less is known about its effect on intensive care. This retrospective cohort study at a university hospital showed that in the last 6 months of life, palliative care significantly reduced intensive care unit (ICU) and hospital admissions, reduced deaths in the hospital, and increased hospice enrollment. It did not, however, change patients' experiences within the ICU, such as number of procedures, code status, length of stay, or disposition. The findings further support that palliative care exerts its benefit before, rather than during, the ICU setting., (© AlphaMed Press 2017.)

Tumor expression of programmed cell death ligand 1 (PD-L1) is associated with immune evasion in a variety of malignancies, including a subset of triple-negative breast carcinomas, and may mark cancers as susceptible to PD-1/PD-L1 inhibitor therapies. We herein characterize PD-L1 expression in breast cancers across the full range of histomorphologies and investigate its intratumoral heterogeneity and fidelity across primaries and metastases. A total of 245 primary and 40 metastatic (20 nodal, 20 distant) breast carcinomas were evaluated with PD-L1 immunohistochemistry on tissue microarray. Tumor PD-L1 staining was seen in 12% of all primaries including 32% of triple-negative cancers. Staining was common in ductal cancers with medullary (54%), apocrine (27%), and metaplastic features (40%). However, diffuse (>50%) staining was rare (2% of all cancers and 5% of triple negatives). Immune staining was seen in 29% of all primaries and 61% of triple negatives. Tumor expression of PD-L1 was conserved in 94% of matched primary/metastasis pairs, while immune staining showed fidelity in 71%; the remaining cases acquired PD-L1 immune cell expression in the metastasis. Only half of cases with positive tumor staining showed concordance across all analyzed cores. These data demonstrate that PD-L1 expression is prevalent among high-grade, hormone receptor-negative breast cancers with a range of histomorphologies and shows fidelity between primary and metastatic sites in treatment-naive cancers, although acquisition of immune PD-L1 staining in metastases is not uncommon. There is considerable intratumoral heterogeneity in PD-L1 expression, undermining the suitability of core biopsy in the determination of PD-L1 status. Clinical trials are needed to determine PD-L1 staining thresholds required for therapeutic response, as diffuse staining is rare.

Orbital metastases from breast cancer (BC) are rare, but often debilitating. BC accounts for nearly half of metastases to the orbit. Orbital metastases may be discovered years after the initial diagnosis of BC, and are rare at initial presentation. A search of the institutional data base at an academic cancer center identified BC patients who developed or presented with orbital metastases from 2000 to 2013. Baseline characteristics, treatment modalities, survival and treatment responses were collected from the electronic medical record. There were 20 patients identified with orbital metastases (0.7% of all BC cases). The median age at diagnosis of BC was 49 years; 80% had estrogen positive disease. The interval between the initial diagnosis of BC and the presentation of orbital metastases was 8.5 years (0-19 years). Orbital disease was the initial presentation of BC in two cases. Three patients developed bilateral orbital metastases and seven had accompanying brain metastases. The most common presentation was decreased vision (55%), followed by diplopia (25%). The median survival after orbital metastases was 24 months. Thirteen patients (65%) received local radiation therapy. Of those radiated, 90% reported improvement of orbital symptoms. Other treatments included intraocular bevacizumab, surgery, and systemic therapy. Orbital metastases tend to occur in estrogen receptor positive disease and are often found years after BC onset. Orbital metastases may be associated with the development of brain metastases. Radiotherapy is the preferred local therapy and had high symptom control in this cohort. Oncologists should be aware of the signs of orbital metastases and the treatment options., (© 2016 Wiley Periodicals, Inc.)

Purpose: Patients with advanced cancer typically demonstrate sharp deterioration in physical function and psychological status during the last months of life. This study evaluates the relationship between survival in patients with advanced cancer and longitudinal assessment of anxiety, depression, fatigue, pain interference, and/or physical function using the US National Institute of Health Patient Reported Outcomes Information System., Methods: Mixed-effects models were used to evaluate patient-reported outcome trajectories over time among patients with advanced loco-regional or metastatic cancer receiving care in a hospital-based palliative care clinic. Cox regression analysis was used to assess the statistical significance of differences in the probability of survival associated with patient-reported outcome scores., Results: A total of 472 patients completed 1992 assessments during the 18-month study period. Longitudinal scores for fatigue, pain interference, and physical function demonstrated statistically significant non-linear trajectories. Scores for depression, fatigue, pain interference, and physical function were highly statistically significant predictors of survival (p < 0.01). Clinically meaningful differences in the probability of survival were demonstrated between patients with scores at the 25th vs. 75th percentiles, with absolute differences in survival at 6 and 12 months after assessment from 10 to 18 percentage points., Conclusions: Patient-reported outcomes can be used to reliably estimate where patients are along the trajectory of deteriorating health status leading toward the end of life, and for identifying patients with declining symptoms in need of referral to palliative care or more aggressive symptom management.

Background: Adenoid cystic carcinoma (ACC) is a rare tumor of secretory glands. In this study, recent advances in molecular characterization and in therapeutics are reviewed., Methods: A search of articles in PubMed and of abstracts from national meetings was performed regarding ACC., Results: Recent genetic analyses found that recurrent chromosome 6:9 translocations in ACC generate an MYB:NFIB gene fusion resulting in overexpression of the MYB oncoprotein. Several other frequent mutations are recently published that may be relevant for drug development. Several trials of targeted drugs are reviewed. Some agents delay tumor progression, but tumor responses remain rare., Conclusion: ACCs have a characteristic chromosomal translocation, but also frequently pick up additional mutations. Clinical research is limited by the rarity and slow growth of ACC. Several ongoing trials are testing agents that inhibit fibroblast growth factor receptor signaling or other signaling pathways. Novel treatments based on the recently sequenced tumor genome are under development., (© 2015 Wiley Periodicals, Inc.)

Background: The predominant breast cancer subtypes, invasive lobular carcinoma (ILC) and invasive ductal carcinoma (IDC), have similar recurrence and survival rates but differing patterns of metastatic recurrence., Methods: A retrospective review of breast cancers treated at an academic medical center from 1999 to 2012 was performed. Demographic, pathologic, treatment, and follow-up data were collected for 179 ILC and 358 IDC patients (1:2 stage-matched). The median follow-up was 4.7 years., Results: The baseline characteristics were similar in the two groups. ILC was more likely to be hormone-receptor-positive/HER2-negative and mammographically occult. The number of surgical resections, breast conservation rate, systemic treatment, and taxane use was similar between the groups. The overall recurrence rate was the same. ILC recurred more often in the abdominal cavity (24.3% in ILC vs. 4.1% in IDC, p = 0.001). The disease-free survival and overall survival were equal. On multivariate analysis, age, stage of disease, hormone receptor status, and systemic therapy were associated with survival, but histology was not., Conclusions: Compared to ductal breast cancers, lobular breast cancers recur more often in the abdominal cavity. Both ILC and IDC have comparable surgical and medical treatment outcomes and survival. Our data suggest that enhanced surveillance and imaging might be useful in ILC., (© 2016 S. Karger AG, Basel.)

Background: Tubular carcinoma (TC) of the breast is an uncommon, well-differentiated subtype of breast cancer with an excellent prognosis, but ambiguity in how it should be defined and treated., Objective: To determine the clinicopathologic characteristics and survival outcomes of patients with TC., Methods: The University of Virginia (UVA) Breast Cancer Database and the Surveillance, Epidemiology and End Results (SEER) databases were queried for patients with either grade 1 TC or grade 1 ductal (G1D) breast cancer., Results: Nineteen institutional TC cases were identified and compared to 54 G1D cases. Flat epithelial atypia frequently was found with TC and not with G1D. There was no difference in overall or progression free survival. In SEER 18, 9,565 cases of TC were found. Most cases were stage I and patient characteristics were nearly identical. Both cause specific survival and overall survival were significantly longer for TC when compared to G1D., Conclusions: This review shows TC to have favorable behavior, with similar features to, but superior survival compared to low-grade ductal carcinoma of the breast. This suggests the adequacy of histopathologic review while reinforcing the designation of TC as a unique subtype.

IMPORTANCE Previous studies have reported that histopathologically amelanotic melanoma is associated with poorer survival than pigmented melanoma; however, small numbers of amelanotic melanomas, selected populations, lack of centralized pathologic review, or no adjustment for stage limit the interpretation or generalization of results from prior studies.OBJECTIVE To compare melanoma-specific survival between patients with histopathologically amelanotic and those with pigmented melanoma in a large international population-based study.DESIGN, SETTING, AND PARTICIPANTS Survival analysis with a median follow-up of 7.6 years.The study population comprised 2995 patients with 3486 invasive primary melanomas centrally scored for histologic pigmentation from the Genes, Environment, and Melanoma(GEM) Study, which enrolled incident cases of melanoma diagnosed in 1998 through 2003 from international population-based cancer registries.MAIN OUTCOMES AND MEASURES Clinicopathologic predictors and melanoma-specific survival of histologically amelanotic and pigmented melanoma were compared using generalized estimating equations and Cox regression models, respectively.RESULTS Of 3467 melanomas, 275 (8%) were histopathologically amelanotic. Female sex,nodular and unclassified or other histologic subtypes, increased Breslow thickness, presence of mitoses, severe solar elastosis, and lack of a coexisting nevus were independently associated with amelanotic melanoma (each P < .05). Amelanotic melanoma was generally ofa higher American Joint Committee on Cancer (AJCC) tumor stage at diagnosis (odds ratios[ORs] [95%CIs] between 2.9 [1.8-4.6] and 11.1 [5.8-21.2] for tumor stages between T1b and T3b and ORs [95%CIs] of 24.6 [13.6-44.4] for T4a and 29.1 [15.5-54.9] for T4b relative to T1a;P value for trend, <.001) than pigmented melanoma. Hazard of death from melanoma was higher for amelanotic than for pigmented melanoma (hazard ratio [HR], 2.0; 95%CI, 1.4-3.0)(P < .001), adjusted for age, sex, anatomic site, and study design variables, but survival did not differ once AJCC tumor stage was also taken into account (HR, 0.8; 95%CI, 0.5-1.2)(P = .36).CONCLUSIONS AND RELEVANCE At the population level, survival after diagnosis of amelanotic melanoma is poorer than after pigmented melanoma because of its more advanced stage at diagnosis. It is probable that amelanotic melanomas present at more advanced tumor stages because they are difficult to diagnose. The association of amelanotic melanoma with presence of mitoses independently of Breslow thickness and other clinicopathologic characteristics suggests that amelanotic melanomas might also grow faster than pigmented melanomas. New strategies for early diagnosis and investigation of the biological properties of amelanotic melanoma are warranted.

Background: Cancers produce soluble and cell-associated molecules that can suppress or alter antitumor immunity. Preclinical studies suggest the disease burden may alter the cytokine profile of helper T cell responses to cancer antigens. We studied cytokine production by helper T cells responding to vaccination with 6 melanoma helper peptides (6MHP) in blood and lymph nodes., Methods: Twenty-three patients with stage IIIB-IV melanoma received a 6MHP vaccine. Antigen-reactive T cells from blood and draining lymph nodes were cultured, exposed to antigen, and then supernatants (days 2 and 5) were assayed for Th1 and Th2 cytokines. Results from 4 time points were compared to pre-vaccine levels., Results: Cytokine responses to vaccinating peptides were observed in 83% of patients. Th1 favoring responses were most common (17 of 19 responders). The most abundant cytokines produced were IFN-γ and IL-5 in the PBMC's. IL-2 responses predominated in cells obtained from draining lymph nodes in 2-day culture but not in 5-day cultures. Patients with clinically measurable disease produced similar levels of total cytokine and similar degree of Th1 polarization as patients with no evidence of disease (NED)., Conclusions: The MHC class II-associated peptides used in this study induced helper T cells with a Th1-biased cytokine response in both PBMC and sentinel immunized nodes. Most patients can mount a Th1 dominant response to these peptides. Future studies are needed to test newer vaccine adjuvants in combination with these peptides., Trial Registration: CDR0000378171, Clinicaltrials: NCT00089219.

Numerous medications have been associated with the development of subacute cutaneous lupus erythematosus. A mechanism explaining how unrelated drug classes can lead to subacute cutaneous lupus erythematosus has remained elusive, suggesting that there may be multiple etiologic pathways. Taxanes (docetaxel, paclitaxel, and cabazitaxel) inhibit cell mitosis through microtubule stabilization and their use has uncommonly been associated with subacute cutaneous lupus erythematosus. Recently the antigen recognized by anti-Ro/SS-A antibody (Ro52) has been localized to the cytoplasmic microtubule network. A case report of docetaxel exacerbated subacute cutaneous lupus erythematosus is presented and literature review performed, revealing 11 additional cases of taxane associated subacute cutaneous lupus erythematosus. Taxanes are proposed to exacerbate or induce subacute cutaneous lupus erythematosus in immunogenetically predisposed patients by stabilizing microtubules and affecting Ro/SS-A antigen (Ro52) expression. This may be an under recognized adverse drug reaction because taxanes are used for a defined period and the cutaneous eruption tends to spontaneously improve. Studies analyzing how particular drug classes affect Ro/SS-A antigen expression may be useful in identifying mechanisms of action in drug-induced subacute cutaneous lupus erythematosus.

Purpose: Anticancer drug development is inefficient, but genetically engineered murine models (GEMM) and orthotopic, syngeneic transplants (OST) of cancer may offer advantages to in vitro and xenograft systems., Experimental Design: We assessed the activity of 16 treatment regimens in a RAS-driven, Ink4a/Arf-deficient melanoma GEMM. In addition, we tested a subset of treatment regimens in three breast cancer models representing distinct breast cancer subtypes: claudin-low (T11 OST), basal-like (C3-TAg GEMM), and luminal B (MMTV-Neu GEMM)., Results: Like human RAS-mutant melanoma, the melanoma GEMM was refractory to chemotherapy and single-agent small molecule therapies. Combined treatment with AZD6244 [mitogen-activated protein-extracellular signal-regulated kinase kinase (MEK) inhibitor] and BEZ235 [dual phosphoinositide-3 kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor] was the only treatment regimen to exhibit significant antitumor activity, showed by marked tumor regression and improved survival. Given the surprising activity of the "AZD/BEZ" combination in the melanoma GEMM, we next tested this regimen in the "claudin-low" breast cancer model that shares gene expression features with melanoma. The AZD/BEZ regimen also exhibited significant activity in this model, leading us to testing in even more diverse GEMMs of basal-like and luminal breast cancer. The AZD/BEZ combination was highly active in these distinct breast cancer models, showing equal or greater efficacy compared with any other regimen tested in studies of over 700 tumor-bearing mice. This regimen even exhibited activity in lapatinib-resistant HER2(+) tumors., Conclusion: These results show the use of credentialed murine models for large-scale efficacy testing of diverse anticancer regimens and predict that combinations of PI3K/mTOR and MEK inhibitors will show antitumor activity in a wide range of human malignancies.

Objective: Estrogen treatment limits the cytotoxic effects of chemotherapy in estrogen receptor-positive (ER+) breast cancer cell lines, suggesting that estrogen pathway signaling may confer chemotherapeutic resistance. This study investigates the molecular responses of ER+ breast cancer cell lines to the chemotherapeutic agent, doxorubicin, in the presence or absence of estrogen., Methods: ER+ MCF-7 and T47-D cells were cultured in hormone-starved or estrogen-containing media with or without doxorubicin at concentrations mimicking the low concentrations seen in plasma and tumor microenvironments in humans following typical bolus administration. Protein levels, phosphorylations, and interactions of estrogen-signaling molecules were assessed following these treatments, as well the effects of ER signaling inhibitors on cell proliferation., Results: Surprisingly, estrogen and doxorubicin co-treatment markedly induced pro-growth alterations compared to doxorubicin alone and modestly enhanced estrogen alone-induced changes. Several inhibitors suppressed cell proliferation in the presence of doxorubicin and estrogen., Conclusions: These findings demonstrate that molecular changes caused by doxorubicin in ER+ breast cancer cells can be reversed by estrogen, providing molecular evidence for the poorer responses of ER+ tumors to doxorubicin in the presence of physiologic estrogen levels. Our results also suggest that the addition of drugs targeting the ER, EGFR, the SFKs, MEK, PI3K, and/or the MMP proteins to a conventional chemotherapy regimen may improve chemosensitivity., (Copyright © 2012 S. Karger AG, Basel.)

Background: Rodent studies are a vital step in the development of novel anticancer therapeutics and are used in pharmacokinetic (PK), toxicology, and efficacy studies. Traditionally, anticancer drug development has relied on xenograft implantation of human cancer cell lines in immunocompromised mice for efficacy screening of a candidate compound. The usefulness of xenograft models for efficacy testing, however, has been questioned, whereas genetically engineered mouse models (GEMMs) and orthotopic syngeneic transplants (OSTs) may offer some advantages for efficacy assessment. A critical factor influencing the predictability of rodent tumor models is drug PKs, but a comprehensive comparison of plasma and tumor PK parameters among xenograft models, OSTs, GEMMs, and human patients has not been performed., Methods: In this work, we evaluated the plasma and tumor dispositions of an antimelanoma agent, carboplatin, in patients with cutaneous melanoma compared with four different murine melanoma models (one GEMM, one human cell line xenograft, and two OSTs)., Results: Using microdialysis to sample carboplatin tumor disposition, we found that OSTs and xenografts were poor predictors of drug exposure in human tumors, whereas the GEMM model exhibited PK parameters similar to those seen in human tumors., Conclusions: The tumor PKs of carboplatin in a GEMM of melanoma more closely resembles the tumor disposition in patients with melanoma than transplanted tumor models. GEMMs show promise in becoming an improved prediction model for intratumoral PKs and response in patients with solid tumors.

This study focuses on ways that the size distribution of individuals influences the types and intensities of competitive interactions within a population of aquatic arthropod predators. Three field experiments and one laboratory experiment were designed to test for feeding interference, interference mortality, and dispersal effects within and between larval size classes of the primarily semivoltine dragonfly Tetragoneuria cynosura in Bays Mountain Lake. One field experiment documented the temporal pattern of colonization of large-mesh cylinders by the small, first-year-class larvae during a 30-day period; the results are consistent with passive (density-independent) colonization. A second field experiment examined the effect of large, second-year-class larvae at densities of 1 or 3 per cylinder (14 or 42 m -2 ) on colonization by small larvae; this colonization was inhibited at the high density of large larvae. In the laboratory experiment, when larvae of the two size-classes were together in the same aquarium, small larvae moved around less than when by themselves (dispersal inhibition). Thus the inhibition of colonization observed in the field may result from interference mortality, rather than from a flight response to the presence of larger conspecifics.To evaluate this interpretation, the third field experiment measured the in-situ functional response of large larvae to each other and to their small conspecific prey. Results suggest a type 1 (linear) functional response, with feeding inteference among large larvae. Moreover, the interference mortality inflicted by larger larvae on smaller conspecifics was apparently more intense on larger individuals within the small size-class. Taken together, the three field experiments and a statistical power analysis show how colonization and interference interact to determine the local density of small larvae, and why such interference effects are difficult to detect experimentally in the field.