Antibody-based therapy has revitalized the world of cancer therapeutics since rituximab was first approved for the treatment of Non-Hodgkin’s Lymphoma. Monoclonal antibodies against cancer antigens have been successful strategies for only a handful of cancer types due to many reasons including lack of antibody specificity and complex nature of tumor milieu which interfere with antibody efficacy. Polyspecific antibodies are promising class of anti-cancer agents which can be directed at multiple tumor antigens to eradicate tumor cells more precisely and effectively. They may overcome some of these limitations and have already changed treatment landscape for some malignancies such as B cell acute lymphoblastic leukemia. Pre-clinical studies and early phase clinical trials have demonstrated that this approach may be an effective strategy even for solid tumors. This review focuses on the development of bispecific and trispecific antibody therapy for the treatment of solid tumor malignancies and highlights the potential they hold for future therapies to come.

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Trastuzumab is a monoclonal antibody targeted against the HER2 tyrosine kinase receptor. Although trastuzumab is a very active agent in HER2-overexpressing breast cancer, the majority of patients with metastatic HER2-overexpressing breast cancer who initially respond to trastuzumab develop resistance within 1 year of initiation of treatment and, in the adjuvant setting, progress despite trastuzumab-based therapy. The antibody-drug conjugate trastuzumab-DM1 (T-DM1) was designed to combine the biological activity of trastuzumab with the targeted delivery of a highly potent antimicrotubule agent, DM1 (N-methyl-N-[3-mercapto-1-oxopropyl]-l-alanine ester of maytansinol), a maytansine derivative, to HER2-overexpressing breast cancer cells. T-DM1 is the first antibody-drug conjugate with a nonreducible thioether linker in clinical trials. Phase I and II clinical trials of T-DM1 as a single agent and in combination with paclitaxel, docetaxel and pertuzumab have shown clinical activity and a favorable safety profile in patients with HER2-positive metastatic breast cancer. Two randomized phase III trials of T-DM1 are awaiting final results; the EMILIA trial is evaluating T-DM1 compared with lapatinib plus capecitabine, and early positive results have been reported. The MARIANNE trial is evaluating T-DM1 plus placebo versus T-DM1 plus pertuzumab versus trastuzumab plus a taxane. Here, we summarize evidence from clinical studies and discuss the potential clinical implications of T-DM1.

Although platinum based therapy has improved short term survival of patients with metastatic ovarian cancer, the majority of patients continue to relapse and eventually die of their disease. Currently, a plethora of agents are in development, but how to combine them to enhance efficacy remains largely empiric. We have used short in vitro culture of defined cell lines with application of promising agents and analysis for cell death using a MTT assay to identify potentially useful combinations. Using median effect analysis, curve shift analysis and apoptosis assays, we can identify when agents are synergistic or antagonistic when applied together. Up to three agents can be studied in combination. Using three cell lines: SK-OV3, CaOV-3, and ES-2 (a clear cell tumor), we have identified that panobinostat (LBH-589), a broad histone deacetylase inhibitor in clinical trials, demonstrates global synergy with gemcitabine, with paclitaxel, and additive to synergistic effects with 5'DFUR. The triplet of panobinostat, doxorubicin, and carboplatin is especially synergistic in these cell lines. These effects are cytotoxic and not cytostatic. As all these agents are used clinically, we have identified combinations which warrant further investigation.

We report a case of malignant ovarian steroid cell tumor not otherwise specified (NOS) in a 47-year-old female who presented with hirsutism, virilization, and amenorrhea. At the time of laparotomy, the tumor had already spread to the pelvic cul-de-sac. She underwent a total hysterectomy, bilateral salpingo-oophorectomy, and tumor resection with no residual disease. She received three cycles of bleomycin, etoposide, and cisplatin (BEP) and is now free of disease 24 months after surgery. Literature review of ovarian steroid cell tumors NOS including clinicopathological features and clinical management was performed.

Persons over the age of 65 years are the fastest growing segment of the US population. In the next 30 years this segment will represent more than 20% of the population. Fifty percent of all cancers occur in this age group and therefore the total cancer burden is expected to rise. Data are becoming available that will better guide the use of chemotherapy in the older patient population. Studies are presented discussing pharmacokinetic data on a number of chemotherapeutic agents with an emphasis on those that have entered clinical practice over the past few years. Many of these agents seem to have a beneficial therapeutic index, particularly in regard to older patients. Aging can affect the pharmacokinetics of chemotherapy in a number of ways. Absorption is only modified minimally by age. The greater concern with the use of oral drugs is patient compliance. Volume of distribution is affected by changes in body composition, anaemia and decreased plasma albumin concentration. There are many drugs in which renal excretion plays an important role. Decline in glomerular filtration is a consistent phenomenon with aging. Drug metabolism is primarily affected by changes in the P450 system and coadministration of drugs which also interact with this important enzyme system. The selection of chemotherapy in the elderly is frequently determined by degree of comorbidity and the patients' functional status. These factors are critical and can often determine response and toxicity. This article discusses the changes that occur with antimetabolites, camptothecins, anthracyclines, taxanes, platinum compounds, epipodophyllotoxins and vinca alkaloids. There has also been an increasing trend toward the use of oral chemotherapy. Factors that must be considered in selecting chemotherapeutic agents include limitations of saturability of absorption, patient compliance and the pharmacokinetic and pharmacodynamic changes that occur in older patients. Interpatient variability and age-related changes in drug metabolism are discussed. Careful attention to the physiological changes with age and dose adjustments necessary for end-organ dysfunction (renal, hepatic) are needed to ensure the safe administration of chemotherapy. In this article specific diseases are discussed (breast, colon, ovarian and non-small lung cancers) with recommendations for drug selection in adjuvant chemotherapy and the treatment of metastatic disease. Future studies will need to incorporate these various factors to properly evaluate chemotherapy in older patients. Research and educational initiatives targeted to this population will need to be a priority.

PURPOSE Homologous recombination deficiency, identified by homologous recombination deficiency gene alterations or high percentage of genome-wide loss of heterozygosity (gLOH), is associated with improved prognosis, platinum sensitivity (PS), and poly (ADP-ribose) polymerase inhibitor response in high-grade ovarian cancer. Since the copy number–high (CN-H) endometrial cancer molecular subtype (EC-MS) shares molecular features with high-grade ovarian cancer, our aim was to assign EC-MS on the basis of comprehensive genomic profiling (CGP) results and evaluate the gLOH status with clinical behavior of EC. METHODS Eighty-two epithelial EC tumor tissues were sequenced by hybrid capture–based CGP, and results were used to assign EC-MS (ultramutated, microsatellite instability–high, CN-low; CN-high). Retrospective chart review established clinical characteristics, including PS. Relationships of PS, EC-MS, gene alterations, and gLOH were assessed statistically. RESULTS PS and EC-MS of CN-H showed statistically significant difference in overall survival (OS). Most notably, when the CN-H EC-MS was subcategorized by gLOH status, there was a significant difference in OS with gLOH-H being associated with longer survival. Cox semi-proportional hazard modeling showed that gLOH, stage, and race were significant in modeling OS. CONCLUSION The method of assigning EC-MS by CGP demonstrates similar clinical features to previous reports of EC-MS assigned by other methods. CGP can also assess gLOH status with gLOH-H most commonly seen in CN-H tumors. CN-H, gLOH-H patients showed significantly improved OS (hazard ratio, 0.100 [0.20-0.51 95% CI]). Thus, gLOH status may be a meaningful prognostic biomarker within the CN-H tumors and possibly across EC-MS.

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