A Pilot Study of the Combination of Entinostat with Capecitabine in Advanced Breast Cancer.

Background: Breast cancer has an unacceptably high recurrence rate when any residual disease is found following neoadjuvant treatment of high-risk disease. Based on clinical data suggesting an adjuvant role for epigenetic modifying agents in breast cancer and preclinical data suggesting synergistic activity of entinostat combined with capecitabine, we conducted a phase I, open-label study of these agents in metastatic breast cancer (MBC). Both agents have published doses for use in combination therapy, but the agents had not previously been combined with each other in a human trial. Methods: A multisite phase I dose escalation study was performed at two academic centers. Patients with pretreated, HER2-negative MBC, and measurable disease were enrolled. Dual dose escalation was performed via a Bayesian partial order continual assessment method. Dose levels ranged from entinostat 3 mg to 5 mg and capecitabine 800 mg/m2 to 1000 mg/m2. Results: Thirteen patients with MBC and a median of 4 lines of prior therapy were enrolled across four dose level combinations. The most common toxicities were neutropenia, thrombocytopenia, and palmar-plantar dysesthesia, which were expected toxicities. No new safety signals were observed. One dose-limiting toxicity was observed, which did not exceed a prespecified toxicity rate of 25%. The median treatment duration was 2.37 months. No partial nor complete responses were observed. The study was halted early prior to entering an expansion phase, due to drug supply limitations. Conclusion: The tested dosing combinations of entinostat and capecitabine are likely safe in heavily pretreated metastatic breast cancer. This study's clinical investigation of entinostat in breast cancer was halted, but drug development of this agent continues outside the US. There remains a need for postoperative adjuvant drug therapy for the subpopulation of breast cancer patients with high-risk residual cancer after curative therapy. This trial is registered with NCT03473639.

Cryotherapy for prevention of chemotherapy induced peripheral neuropathy in breast cancer.

Peripheral neuropathy is a well-described complication of chemotherapy. There are no known treatments to reverse peripheral neuropathy. Chemotherapy-induced peripheral neuropathy is a dose-limiting toxicity in cancer treatment and is debilitating. Cryotherapy, or the use of cold garments/ice bags applied to extremities during chemotherapy, is a method to prevent or minimize treatment related neuropathy. There is no standard method of providing cryotherapy currently. A review of the literature was performed revealing that a variety of cryotherapy methods exist. While small studies suggest potential preventive effect of some forms of cryotherapy, consistent results from well-designed randomized studies are lacking. A small benefit from the use of cryotherapy to prevent peripheral neuropathy might exist, but conflicting studies exist. In light of the low cost to implement ice bags during chemotherapy and the low risk of toxicity, the use of ice bags may be reasonable during taxane chemotherapy for the treatment of breast cancer.

Estrogen receptor positive breast cancer: contemporary nuances to sequencing therapy.

The treatment landscape of hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer has evolved dramatically in recent years. While the combination of endocrine therapy and a cyclin-dependent kinase 4/6 inhibitor is accepted as standard first-line treatment in most settings without visceral crisis, newer therapies have challenged traditional treatment models where cytotoxic chemotherapy was previously felt to be the only second-line option at time of progression. The incorporation of next-generation sequencing has led to the identification of molecular targets for therapeutic agents, including phosphatidylinositol 3-kinase and ESR1, though similar pathways can be targeted even in the absence of a mutation, such as with use of inhibitors of mammalian target of rapamycin. Current data also supports the use of cyclin-dependent kinase inhibitors beyond progression, even prior to the patient's first introduction to chemotherapy. The abundance of therapeutic options not only delay time to cytotoxic chemotherapy and antibody-drug conjugate initiation, but has resulted in improvement in breast cancer survivorship. Many unanswered questions remain, however, as to the most efficacious way to sequence these novel agents. To assist in this decision-making, we will review the existing data on systemic therapy and propose a treatment paradigm.

Evaluating Nelipepimut-S in the Treatment of Breast Cancer: A Short Report on the Emerging Data.

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.

Efficient dose-finding for drug combination studies involving a shift in study populations.

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.

Radiographically Occult Carcinomatous Spread of Breast Cancer to the Liver: A Challenging Case.

Metastatic carcinomatosis to the liver is a pattern of malignant infiltration that tends to provoke hepatic fibrosis. It is a rare complication of multiple solid tumor types and often seen in the absence of discrete tumor mass in the liver. We report a case of a 69-year-old woman with metastatic ductal carcinoma of the breast who presented with rising serum tumor markers and mildly cirrhotic contour of the liver on a CT scan. An early diagnosis of occult spread to the liver was made by means of a percutaneous liver biopsy showing desmoplastic response to invasive breast cancer cells found diffusely in the liver. This case highlights a rare pattern of metastatic spread of breast cancer as well as predisposing and prognostic features.

A pilot study of the immunogenicity of a 9-peptide breast cancer vaccine plus poly-ICLC in early stage breast cancer.

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.

Pure Apocrine Carcinomas Represent a Clinicopathologically Distinct Androgen Receptor-Positive Subset of Triple-Negative Breast Cancers.

Apocrine carcinomas comprise ∼1% of all breast cancers and are characterized by large cells bearing abundant eosinophilic granular cytoplasm, round nuclei, and prominent nucleoli. They are typically estrogen receptor/progesterone receptor/HER2 negative, making them unresponsive to typical hormonal or HER2-based chemotherapy. However, this subtype of triple-negative breast cancers expresses androgen receptor (AR), a feature not shared by most nonapocrine triple-negative cancers (NA-TNCs). AR therefore represents a potential diagnostic tool and therapeutic target for apocrine breast carcinoma. All pure apocrine carcinomas diagnosed during a 10-year period were reviewed, and clinicopathologic characteristics were compared with a control group of 26 NA-TNC cases. Twenty apocrine carcinomas were identified (∼0.8% of all breast cancers). The mean age at diagnosis was 69.3 years for apocrine carcinomas and 56.7 years for NA-TNC. All apocrine carcinomas and no NA-TNC were AR positive. The proportions of apocrine carcinoma grades varied, with G1 being seen in 15% of patients, G2 in 55%, and G3 in 30%. In contrast, 100% of NA-TNC cases were G3. The majority of apocrine carcinomas presented at low T stage (T1: 70%; T2: 20%; T3: 10%; T4: 0%), whereas NA-TNC cases more often presented at T2 or higher (T1: 46.2%; T2: 30.8%; T3: 11.5%; T4: 11.5%). Thirty percent of apocrine carcinomas and 30.8% of NA-TNCs had nodal metastases at presentation. Apocrine carcinomas had a favorable clinical prognosis, with 80% of patients showing no evidence of disease-related morbidity or mortality (mean follow-up: 45.2 mo). Pure apocrine carcinomas represent a clinicopathologically distinct subgroup of triple-negative breast cancer characterized by AR positivity. When compared with NA-TNC, apocrine carcinomas more often present in older women with lower grade and T stage, a group in which a more conservative treatment regimen is often desired.

A phase II study of UCN-01 in combination with irinotecan in patients with metastatic triple negative breast cancer.

Mutations in TP53 lead to a defective G1 checkpoint and the dependence on checkpoint kinase 1 (Chk1) for G2 or S phase arrest in response to DNA damage. In preclinical studies, Chk1 inhibition resulted in enhanced cytotoxicity of several chemotherapeutic agents. The high frequency of TP53 mutations in triple negative breast cancer (TNBC: negative for estrogen receptor, progesterone receptor, and HER2) make Chk1 an attractive therapeutic target. UCN-01, a non-selective Chk1 inhibitor, combined with irinotecan demonstrated activity in advanced TNBC in our Phase I study. The goal of this trial was to further evaluate this treatment in women with TNBC. Patients with metastatic TNBC previously treated with anthracyclines and taxanes received irinotecan (100-125 mg/m(2) IV days 1, 8, 15, 22) and UCN-01 (70 mg/m(2) IV day 2, 35 mg/m(2) day 23 and subsequent doses) every 42-day cycle. Peripheral blood mononuclear cells (PBMC) and tumor specimens were collected. Twenty five patients were enrolled. The overall response (complete response (CR) + partial response (PR)) rate was 4 %. The clinical benefit rate (CR + PR + stable disease ≥6 months) was 12 %. Since UCN-01 inhibits PDK1, phosphorylated ribosomal protein S6 (pS6) in PBMC was assessed. Although reduced 24 h post UCN-01, pS6 levels rose to baseline by day 8, indicating loss of UCN-01 bioavailability. Immunostains of γH2AX and pChk1(S296) on serial tumor biopsies from four patients demonstrated an induction of DNA damage and Chk1 activation following irinotecan. However, Chk1 inhibition by UCN-01 was not observed in all tumors. Most tumors were basal-like (69 %), and carried mutations in TP53 (53 %). Median overall survival in patients with TP53 mutant tumors was poor compared to wild type (5.5 vs. 20.3 months, p = 0.004). This regimen had limited activity in TNBC. Inconsistent Chk1 inhibition was likely due to the pharmacokinetics of UCN-01. TP53 mutations were associated with a poor prognosis in metastatic TNBC.

Unresectable cholangiocarcinoma: comparison of survival in biliary stenting alone versus stenting with photodynamic therapy.

BACKGROUND & AIMS: Photodynamic therapy (PDT) for unresectable cholangiocarcinoma is associated with improvement in cholestasis, quality of life, and potentially survival. We compared survival in patients with unresectable cholangiocarcinoma undergoing endoscopic retrograde cholangiopancreatography (ERCP) with PDT and stent placement with a group undergoing ERCP with stent placement alone. METHODS: Forty-eight patients were palliated for unresectable cholangiocarcinoma during a 5-year period. Nineteen were treated with PDT and stents; 29 patients treated with biliary stents alone served as a control group. Multivariate analysis was performed by using Model for End-Stage Liver Disease score, age, treatment by chemotherapy or radiation, and number of ERCP procedures and PDT sessions to detect predictors of survival. RESULTS: Kaplan-Meier analysis demonstrated improved survival in the PDT group compared with the stent only group (16.2 vs 7.4 months, P<.004). Mortality in the PDT group at 3, 6, and 12 months was 0%, 16%, and 56%, respectively. The corresponding mortality in the stent group was 28%, 52%, and 82%, respectively. The difference between the 2 groups was significant at 3 months and 6 months but not at 12 months. Only the number of ERCP procedures and number of PDT sessions were significant on multivariate analysis. Adverse events specific to PDT included 3 patients with skin phototoxicity requiring topical therapy only. CONCLUSIONS: ERCP with PDT seems to increase survival in patients with unresectable cholangiocarcinoma when compared with ERCP alone. It remains to be proved whether this effect is attributable to PDT or the number of ERCP sessions. A prospective randomized multicenter study is required to confirm these data.