Monoclonal Antibody Therapy In Patients Research Articles

Emergency Department-based monoclonal antibody therapy for patients with mild to moderate COVID-19

Emergency Department-based monoclonal antibody therapy for patients with mild to moderate COVID-19

Implementation of an Emergency Department-Embedded Infusion Center for the Administration of Monoclonal Antibody Therapy in Patients With Early COVID-19 Infection.

The coronavirus disease 2019 (COVID-19) pandemic has tested nurse staffing and other resources necessary for lifesaving treatment. The emergency use authorization in November 2020 of bamlanivimab as monotherapy and casirivimab/imdevimab as combination therapy brought hope to many as an option for outpatients at risk for severe illness. However, logistical concerns were soon revealed, because safe administration requires a location where patients can receive specialized care and monitoring for a period of 2 hours. This type of therapy would normally be offered at an outpatient infusion center. These centers often serve persons who are immunocompromised, and introducing COVID-19–positive individuals could threaten the safety of this population. This article describes the deployment of an emergency department–embedded infusion center set up for the purpose of supporting community members and providers electing for this treatment option.

465P Identification of actionable alterations in primary colorectal tumors using NGS-based comprehensive genomic profiling

Increasing numbers of actionable alterations have emerged in colorectal cancer. Aside from anti-EGFR monoclonal antibody therapy for patients with KRAS, NRAS, and BRAF wild-type tumors, around 60% of patients could benefit from single or combined targeted therapies. To inform potential therapy options, a next-generation sequencing (NGS)-based comprehensive genomic profiling is essential prior treatment. In this study, we aim to identify rational targeted therapy options in colorectal cancer.

31 Emergency Department-Based Monoclonal Antibody Therapy for Patients With Mild to Moderate COVID-19

Monoclonal antibody therapy (MOAB) has recently emerged as a treatment for mild to moderate COVID-19, potentially preventing those with underlying conditions from progressing to severe illness and hospitalization. While MOAB administration has commonly been restricted to infusion centers or inpatient settings, the infection prevention needs of patients with acute COVID-19 and the ambulatory nature of the therapy make the emergency department (ED) a useful setting to offer this treatment. Further, as EDs are the primary point of health care access for many at-risk individuals, offering MOAB in the ED may increase availability of treatment options for patients from traditionally underserved communities.

Analyzing Risk of Infection with Anti-CD38 Monoclonal Antibody Therapy for Patients with Multiple Myeloma

Monoclonal antibodies targeting CD38 are emerging as a mainstay of therapy for Multiple Myeloma (MM) in the relapse setting as well as upfront. These antibodies not only target CD38 on myeloma cells inducing anti-tumor pleiotropic effects, they also influence normal CD38-expressing cells, including normal plasma cells, natural killer cells and immunosuppressive regulatory cells (van de Donk et al , 2018). These cells play a key role in innate as well as humoral immunity and provide protection against a variety of infectious insults; hence, their depletion in MM patients (pts) can be expected to have deleterious immunological effects due to the dismantling of an effective immune responses in a population already strained by dysfunctional immunity. While it has been previously shown that NK cells decline with exposure to daratumumab (DARA) (Casneuf et al , 2017), its clinical impact on the incidence of infection has yet to be elucidated because clinical trials have shown conflicting results, while POLLUX and CASTOR trials showed generally similar rates of grade 3 or 4 infections (28·3% vs. 22·8% and 21·4% vs. 19·0%, respectively, the ALCYONE trial, reported that grade 3-4 infections were higher in the DARA arm (23·1% vs. 14·7%). Here, we aim to explore the impact of different risk factors on infection during DARA therapy. Methods: We retrospectively reviewed patient records who received DARA-containing regimens for MM between Jan 2016 and Jan 2020. The history of infection, prior therapies, rate of infection during therapy with DARA, hospitalizations, baseline and nadir absolute counts of lymphocyte, monocyte and neutrophil population were extracted. Pts who had less than 1 month of DARA were excluded. Survival was measured from time of DARA start. Survival distribution was estimated using Kaplan-Meier methods and differences of OS, PFS between groups was examined by Wilcoxon test. The effect of treatment on OS and PFS was estimated using a Cox model after controlling for the effects of different variables. Results: Of 123 pts reviewed, median line of therapy was 3 (range: 0-9). Median time from diagnosis was 52 months (range: 0- 232 months). 43 pts (35%) were Black and 77 (63%) Caucasian. Median age was 70 (range 34-94 y/o). 86 (70%) were IgG, 24 were IgA (20%) and 10 light chain myeloma (10%). 24 (20%) had stage I, 37 (30%) had stage II and 61 (50%) had ISS stage III. 66 (53%) pts had transplant as prior therapy and the rest did not undergo transplant. 29 (24%) pts had DARA as a single agent, 66 (53%) in combination with IMiDs and 28 (23%) pts in combination with PI. Median duration of therapy was 133 days (range 30-1245 days). Median ANC 1243 /ml (range: 420-1120). Median ALC 710 /mL (170-8020). Median AMC was 455 /mL (0-2300). 31 pts had history of prior infections and the rest did not. 39 pts had infection during DARA. Overall, there were 125 hospital admission encounters for whole cohort occurred in 36% of cases, more than half of them (55%) were attributable to an infectious process. Bacterial pathogens accounted for the majority of infection. Pts with infection during DARA therapy had statistically significant nadir ALC (median 560 /ml) compared to pts without any infection. The univariate analysis showed age, history of infection, nadir ALC less than 600/ml and number of prior line of therapy as significant factors associated with infection rate during DARA therapy. Multivariate analysis after controlling for these factors shows only Low nadir ALC less than 600 /ml, hazard ratio (HR): 2.15, 95% confidence interval (CI): 1.19-3.76, and history of infection, HR: 1.87, 95% CI: 1.11-2.92, stands out as statistically significant factor. The whole cohort were divided based on ALC<600 during the therapy or history of previous infection; the group with none of these two risk factors was assigned as low risk, the group with either of those as intermediate risk and the pts with both risk factor were characterized as high-risk group (Figure-1). Conclusion: Here we showed that infections is frequent among MM pts treated with DARA-containing regimen and assessed risk factors associated infection during DARA therapy. Dropping ALC and history of prior infection are significant factors associated with higher risk of infection during DARA therapy. These finding suggests vigilance for, and identification of risk factor are warranted for treating MM patient with DARA. The risk model is warranted to be examined in a prospective study. Disclosures de Lima: Pfizer: Other: Personal fees, advisory board, Research Funding; BMS: Other: Personal Fees, advisory board; Incyte: Other: Personal Fees, advisory board; Kadmon: Other: Personal Fees, Advisory board; Celgene: Research Funding. Malek:Cumberland: Research Funding; Takeda: Other: Advisory board , Speakers Bureau; Bluespark: Research Funding; Sanofi: Other: Advisory board; Clegene: Other: Advisory board , Speakers Bureau; Amgen: Honoraria; Medpacto: Research Funding; Janssen: Other: Advisory board, Speakers Bureau.

NUDT15 gene variants and thiopurine-induced leukopenia in patients with inflammatory bowel disease.

Thiopurine has been used to maintain remission and to reduce antidrug antibody formation in monoclonal antibody therapy in patients with inflammatory bowel disease (IBD). The use of thiopurine is limited by side effects such as leukopenia. Thiopurine S-methyltransferase (TPMT) variants are associated with thiopurine-induced leukopenia in Westerners, but the frequency of the risk alleles is low in Asians. Recently, a variant in the nudix hydrolase 15 (NUDT15) gene (R139C, c.415C > T) was reported to be associated with early severe leukopenia in Asians. NUDT15 is an enzyme that converts 6-thio-(deoxy)guanosine triphosphate (6-T(d)GTP) to 6-thio-(deoxy)guanosine monophosphate (6-T(d)GMTP). The R139C variant impairs the stability of the protein and increases incorporation of 6-TGTP and 6-TdGTP into RNA and DNA, respectively, resulting in leukopenia. The frequency of C/C, C/T, and T/T are approximately 80%, 20%, and 1%, respectively in East Asians. Early leukopenia occurred in less than 3% of patients with C/C and in around 20% of those with C/T, whereas it occurred in almost all patients with T/T. Patients homozygous for this variant also develop severe hair loss. The measurement of NUDT15 R139C can increase the safety of thiopurine dramatically and is a successful example of personalized medicine in the field of IBD.

Dual Monoclonal Antibody Therapy in Patients With Systemic AL Amyloidosis and Cardiac Involvement

BackgroundSystemic AL amyloidosis (AL) is a rare disease in which clonal immunoglobulin light chains produced by monoclonal plasma cells circulate and misfold, resulting in direct toxicity and fibrillar deposition of amyloid in numerous tissues. Early mortality from cardiac damage remains high. As depth of organ response carries a prognostic significance, combining anti-plasma cell and anti-amyloid therapies might hold the key to achieving long lasting responses. We report a series of patients who received 2 monoclonal antibodies, anti-CD38 and anti-amyloid, simultaneously. Materials and MethodsWe describe the characteristics and outcomes of 19 patients who received daratumumab (anti-CD38) on progression with front-line therapy for AL, 9 of whom were on concurrent dual monoclonal antibody treatment with daratumumab and NEOD001 (anti-amyloid), and also provide data on the schedule, safety, and tolerability of intravenous infusions of these monoclonal antibodies. ResultsThe 9 patients who received treatment with dual monoclonal antibodies achieved a high rate (100%) of hematologic response in a median of 33 days. There was no significant toxicity to dual monoclonal antibody therapy. Seven of the 8 met criteria for cardiac response, achieved in less than 3 months of combined therapy. Ten patients who received daratumumab alone also had high rates of hematologic and organ responses. ConclusionsMonoclonal antibodies with distinctly different targets can be safely combined in patients with AL and cardiac involvement. Patients experienced high rates of hematologic and cardiac response with combined anti-CD38 and anti-amyloid monoclonal antibody therapies. Further study of this combined approach is warranted.

Adverse events and monitoring requirements associated with monoclonal antibody therapy in patients with multiple sclerosis

Multiple sclerosis (MS) is treated with a variety of immunomodulatory and immunosuppressive drugs. Among the most potent therapeutic options are monoclonal antibodies (MAbs). So far, the MAbs natalizumab, alemtuzumab, and ocrelizumab have been approved for MS treatment. While their efficacy is indisputable, these drugs have safety issues not seen with previous MS drugs. MAbs are the ideal class of treatment for many patients with MS, but neurologists prescribing these MAbs need to be aware of their potential risks and monitor patients closely. Although rare, adverse events associated with MAbs may be fatal; opportunistic infections, tumors, and infusion-related events require planning and monitoring of patients before, during, and after MAb therapy. This review summarizes the type and management of adverse events associated with MAb treatment in patients with MS, and emphasizes the importance of evidence-based knowledge for all neurologists involved in MS therapy.

Calcein release assay as a method for monitoring serum complement activity during monoclonal antibody therapy in patients with B-cell malignancies

Monoclonal antibodies ofatumumab (anti-CD20) and alemtuzumab (anti-CD52) which are approved for usage in patients with chronic lymphocytic leukemia (CLL), efficiently activate the classical complement pathway. However complement is an exhaustible component and high doses of its activators may deplete complement-dependent cytotoxicity (CDC) potential, thus reducing the effect of repeated mAb dosing. Widely used method to measure CDC activity of patients' serum is hemolytic assay (CH50) on sheep erythrocytes. Despite its simplicity, such CH50 assay may not reflect pivotal interactions between patient serum and human complement inhibitors on the surface of target cells. We propose calcein release assay performed on tumor cells similar to those targeted by therapeutic antibodies as an alternative method. We analyzed serum samples collected from 12 patients participating in the clinical study, receiving s.c. 30 mg alemtuzumab three times per week combined with i.v. ofatumumab at an initial dose of 300 mg in week 3 further escalated to 2000 mg every other week. All serum samples were measured by hemolytic assay on sheep erythrocytes as well as using calcein release assay on CD20-positive Raji cells. Our data show that results obtained from both assays are related to each other at the level of the whole group (n = 96 samples, Spearman r = 0.504, p < .001) but may substantially differ when analyzing individual patients. Furthermore, by using CDC assay on Raji cells, we found that in the presented clinical study CDC serum potential was not significantly affected when measured before consecutive administrations in most of the patients.

Telomere length regulation through epidermal growth factor receptor signaling in cancer.

Length of the telomere (TL), a structure at the tip of chromosome that protects and ensures stability, is determined by multi-protein complexes such as telosome/shelterin and telomerase. Earlier studies from our laboratory show that longer TL has potential to be positive predictive biomarker of clinical outcome to anti-epidermal growth factor receptor (EGFR) monoclonal antibody therapy in patients with KRAS WT metastatic colorectal cancer. Although there is extensive literature suggesting the role of shelterin and telomerase, not much literature exists that describes the role of EGFR and KRAS pathway in regulating TL. This detailed review focuses on an insight into various components, including proteins, enzymes and transcription factors, interlinking between EGFR pathways and telomerase that regulate TL.

Clinical Outcomes Related to the Use of Monoclonal Antibody Therapy for Steroid Refractory Acute Graft-Versus Host Disease after Allogeneic Hematopoietic Cell Transplantation

Background: Acute graft versus host disease (aGVHD) is the leading cause of morbidity and mortality following allogenic hematopoietic cell transplantation (HCT). Corticosteroids are the first line treatment although <50% of patients with severe aGVHD (grades III-IV) achieve durable remissions. Monoclonal antibodies (mAb) are often used as second line agents for steroid refractory aGVHD (SR-aGVHD) (Patriarca et. al.; 2004). However, data regarding their tolerability and efficacy is retrospective and limited. We carried out this study to assess the clinical outcomes related to mAb therapy (Infliximab and Tocilizumab) for SR-aGVHD.Methods: Patients with SR-aGVHD that received therapy with either Infliximab or Tocilizumab between January 2003 and May 2016 were retrospectively identified. Clinical grading of aGVHD was per the Glucksberg criteria (Glucksberg et. al.; 1974). SR-aGVHD was defined as any grade progression within 3 days or failure to achieve at least one grade improvement within 7 days of initiation of systemic steroids. Infliximab and Tocilizumab were administered intravenously at 10mg/kg and 8mg/kg weekly for a total of 4 doses, respectively. Clinical response was evaluated at 4 weeks and 12 weeks post mAb treatment. Complete response (CR) was defined as sustained resolution of all clinical signs of aGVHD; partial response (PR) was defined as overall improvement of 1 or more grades; no response (NR) was defined as neither improvement nor worsening of the overall aGVHD grade. Overall response (OR) was defined as either CR or PR. Overall survival (OS) was calculated from the first day of mAb treatment until death or last available follow up.Results: Forty-three patients (median age 54, range 29-74 years; male 67%) with severe SR- aGVHD were included in the study. Of these, 35 (81%) received Infliximab for a median of 4 (range 1-6) cycles and 8 (19%) received Tocilizumab for a median of 3 (range 1-4) cycles. Both groups were comparable with regards to age, gender, conditioning regimen, graft source, degree of HLA match, ABO blood group, CMV incompatibility, and GVHD prophylaxis regimens. Only differences seen were a higher proportion of unrelated donor (p = 0.004) and cord blood HCT (p = 0.031) in the Tocilizumab group. Twenty (57%) of 35 patients treated with Infliximab and 6 (75%) of 8 patients treated with Tocilizumab had an overall aGVHD grade of IV prior to initiation of mAb therapy (p = 0.44). Organ specific distribution and severity of aGVHD are described in table 1.At 4 weeks post mAb therapy, 17 (40%) patients had an OR, 7 (16%) had no response, and 19 (44%) had died. Twenty-six (60%) patients died at 12 weeks, with OR and no response observed in 9 (21%) and 8 (19%) patients, respectively (table 2). Overall response for Tocilizumab versus Infliximab was comparable at 4 weeks (38% vs. 40%; p = 1.0) and at 12 weeks (38% vs. 17%; p = 0.33). Outcomes per aGVHD grade and gastrointestinal-specific stage at 4 weeks and 12 weeks are shown in figures 1-A and 1-B, with organ specific responses shown in figures 1-C and 1-D, respectively. The estimated median OS was 41 (range 4-3837) days for patients treated with Infliximab and 60 (range 10-756) days for those treated with Tocilizumab (p = 0.48). Disease relapse occurred in 5 (11%) patients treated with Infliximab and in none (0%) treated with Tocilizumab (p = 0.56).Thirty-four (79%) patients had infectious complications during and up to one month after mAb therapy. These included 31 (72%) patients with bacterial blood stream infection and 10 (23%) with invasive fungal infections. Overall, infectious complications were comparable (Infliximab - 83% vs. Tocilizumab - 63%; p = 0.33). CMV reactivation occurred in 11 (31%) and in 2 (25%) patients who were treated with Infliximab and Tocilizumab, respectively (p = 1.0). Given the retrospective nature of the study and the concomitant presence of aGVHD, it was difficult to attribute and grade gastrointestinal and hepatobiliary side effects.Conclusions: The use of anti-inflammatory monoclonal antibody therapy in patients with steroid refractory acute GVHD is associated with significant infectious complications (~80%) and poor response rates (~20% at 12 weeks). Current data, limited by a small sample size, does not show any advantages of using Tocilizumab over Infliximab or vice versa. Prospective clinical trials addressing this question are needed. [Display omitted] [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

A link between long-term natalizumab dosing in MS and PML: Putting the puzzle together.

When an infectious serious adverse event is linked with a therapy for an underlying disease, it usually is seen in a few weeks or months, not years. This is not the case with the effective monoclonal antibody therapy for patients with multiple sclerosis (MS) natalizumab (Tysabri), the α4 integrin inhibitor preventing inflammatory T cells entering the brain. The infectious adverse event in patients with MS is another demyelinating disease, progressive multifocal leukoencephalopathy (PML), caused by lytic infection of oligodendrocytes with JC virus (JCV), a ubiquitous agent in the population. Although cases of PML are seen in patients with MS after receiving as few as 7 monthly doses, the highest incidence of PML, 1/75 or higher,1 occurs after 24 monthly doses. Other risk factors for PML in these patients implicate prior exposure to JCV infection evidenced by presence of antiviral antibody as well as previous immunosuppressive treatments.2

Preclinical Evaluation of RA101495, a Potent Cyclic Peptide Inhibitor of C5 for the Treatment of Paroxysmal Nocturnal Hemoglobinuria

Regulation of the terminal phase of the complement component pathway is a clinically validated approach for the therapeutic treatment of complement disorders. Inhibition of complement activation at the C5 level with the monoclonal antibody eculizumab has successfully been used for the treatment of rare disorders such as PNH and aHUS. However, even in these settings there remains a continued unmet need primarily due to need for intravenous administration, lack of activity in patients with C5 mutations and lack of universal access.Ra Pharmaceuticals has developed a macrocyclic synthetic peptide, RA101495, which binds complement C5 with subnanomolar affinity and allosterically inhibits its cleavage into C5a and C5b upon activation of the classical, alternative or lectin pathways. In vitro studies also demonstrated that RA101495 is capable of preventing MAC assembly after thrombin mediated complement activation and is a potent disruptor of the interaction in between C5b and C6.Inhibition of complement activity was evaluated in cynomolgus monkeys following single- and multi-dose subcutaneous (SC) administration. RA101495 exhibited high SC bioavailability and low, single doses fully inhibited complement-mediated hemolytic activity (>95%). Repeat dosing was well tolerated in monkeys and rats at high multiples of the projected human therapeutic dose and resulted in sustained and predictable inhibition of complement activity.RA101495 fully inhibited the hemolysis of erythrocytes from PNH patients after activation of the alternative pathway. The synthetic peptide offers a novel therapeutic approach for inhibiting C5 for the treatment of disorders caused by or associated with complement dysregulation. As a product designed for convenient self-administration, RA101495 should provide an attractive option over monoclonal antibody therapy for patients with PNH and aHUS, including those with C5 polymorphisms and other complement disorders, especially those associated with hypercoagulable states. DisclosuresRicardo:Ra Pharmaceuticals: Employment. Arata:Ra Pharmaceuticals: Employment. DeMarco:Ra Pharmaceuticals: Employment. Dhamnaskar:Ra Pharmaceuticals: Employment. Hammer:Ra Pharmaceuticals: Employment. Fridkis-Hareli:Ra Pharmaceuticals: Consultancy. Rajagopal:Ra Pharmaceuticals: Employment. Seyb:Ra Pharmaceuticals: Employment. Tang:Ra Pharmaceuticals: Employment. Tobe:Ra Pharmaceuticals: Employment. Treco:Ra Pharmaceuticals: Employment.

Anti-Ige monoclonal antibody therapy for the treatment of patients with chronic rhinosinusitis: a multi-disciplinary practice review

Background Several treatment options have been described for chronic rhinosinusitis (CRS), yet many patients remain poorly responsive to medical and surgical therapy. Recently, antiIgE monoclonal antibody has emerged as a potential therapy for CRS. However, to date evidence for its efficacy in this patient population is sparse. The purpose of this study is to evaluate the clinical effect of anti-IgE monoclonal antibody therapy for patients with recalcitrant CRS and asthma treated in a multi-disciplinary clinic.

Abstract 2848: Urinary prostaglandin E metabolite as a biomarker predicting response to EGFR therapy in patients with head and neck cancer

Abstract Background: Cross talk between the epidermal growth factor receptor (EGFR) and prostaglandin E2 pathways (PGE2) is well established. Activation of EGFR signaling can induce PGE2. Urinary PGE-M is a stable end metabolite of PGE2. The purpose of this study was to evaluate the role of urinary PGE-M as a biomarker predicting response to anti-EGFR monoclonal antibody therapy in patients with head and neck squamous cell carcinoma (HNSCC). Patients and Methods: Ten HNSCC patients with recurrent and/or metastatic disease received Nimotuzumab, a humanized monoclonal antibody against EGFR. The response to Nimotuzumab was assessed 2 weeks following the fourth cycle using PERCIST criteria. Urine samples were collected before treatment and 2 weeks after the fourth cycle of therapy. Results: Seven patients had progressive disease (PD) while two patients had stable disease (SD) and one patient had a partial response (PR) to therapy. The mean pretreatment value of urinary PGE-M in patients with SD or PR was 63 ng/mg Cr (range 48-78 ng/mg Cr). By comparison, patients with progressive disease had lower baseline levels of urinary PGE-M with mean pretreatment value of 37ng/mg Cr (range 15- 54ng/mg Cr). More than a 20% reduction in post treatment vs. pretreatment urinary PGE-M values was seen in patients with SD and PR. By comparison, patients with progressive disease had either a minimal reduction or an increase in the post treatment levels of urinary PGE-M. Conclusion: Elevated pretreatment levels of urinary PGE-M may predict response to anti-EGFR therapy in patients with HNSCC. These findings need further validation. Citation Format: Vikram D. Kekatpure, Amritha Suresh, Bharath Rangarajan, Gangotri Siddappa, Moni Abraham Kuriakose. Urinary prostaglandin E metabolite as a biomarker predicting response to EGFR therapy in patients with head and neck cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2848. doi:10.1158/1538-7445.AM2014-2848

Contributions of molecular analysis to the diagnosis and treatment of gastrointestinal neoplasms

This review discusses the role of molecular analysis in the diagnosis and treatment of gastrointestinal (GI) neoplasms. It is divided into 3 sections. The first section describes clinical applications of 11 immunohistochemical stains (p53, HER2, KIT, SDHB, SMAD4, beta-catenin, L-FABP, MLH1, PMS2, MSH2, and MSH6), the results of which directly reflect underlying genetic or epigenetic events. These applications are mainly diagnostic but in a few instances are predictive. Germline mutation testing is a diagnostic cornerstone in the hereditary cancer predisposition syndromes (HCPSs). Section two will describe the genotype and phenotype of 8 HCPSs presenting in the GI tract. Where available, guidelines based on evidence and/or expert opinion as to whom to test are presented. With our ever-expanding knowledge of the molecular genetic basis of cancer and an increasingly "biologic-oriented" therapeutic armamentarium, pathologists play a vital role in directing molecular-based predictive testing. The final section will discuss the 4 most mature examples in the GI tract: (1) HER2 testing to select patients with advanced gastroesophageal adenocarcinoma for anti-HER2 therapy, (2) KIT and PDGFRA mutation analysis to direct tyrosine kinase inhibitor therapy in gastrointestinal stromal tumor, (3) DNA mismatch repair function testing to determine the applicability of adjuvant chemotherapy in patients with stage II colorectal cancer (CRC), and (4) KRAS mutation analysis and related testing to determine the appropriateness of anti-EGFR monoclonal antibody therapy in patients with metastatic CRC.

Trastuzumab emtansine in human epidermal growth factor receptor 2-positive breast cancer

In this review, we aim to update the clinical data of trastuzumab-DM1 (T-DM1) in terms of safety and efficacy, and describe ongoing and future trials evaluating its potential role in the management of patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Trastuzumab emtansine (T-DM1) is an antibody drug conjugate that optimizes delivery of chemotherapy with an anti-HER2 monoclonal antibody. As a conjugate, T-DM1's systemic side effects are significantly minimized due to its targeted delivery by trastuzumab to HER2-positive cells. Phase I and II studies show that the maximum tolerated dose, and thus the recommended dose for T-DM1, is 3.6 mg/kg given intravenously every 3 weeks. Single arm phase Ib/II, II and a randomized phase II first-line study of T-DM1 versus the combination of trastuzumab + docetaxel all showed improved tolerability, and at least equivalent efficacy, compared with our current standard of care. Two randomized phase III registration studies are now active, evaluating this agent in the refractory and first-line HER2-positive settings. T-DM1 has been shown to be a very promising agent for the targeted delivery of chemotherapy and anti-HER2 monoclonal antibody therapy for patients with metastatic, HER2-positive breast cancer. T-DM1 will likely play a role in the management of patients with advanced and early stage HER2-positive breast cancer, but this awaits further study.

Biomarkers predicting clinical response to EGFR-targeted monoclonal antibody therapy in patients with metastatic colorectal cancer

Biomarkers predicting clinical response to EGFR-targeted monoclonal antibody therapy in patients with metastatic colorectal cancer

KRAS Mutations in Primary Colorectal Cancer Tumors and Related Metastases: A Potential Role in Prediction of Lung Metastasis

Background KRAS mutations in colorectal cancer primary tumors predict resistance to anti-Epidermal Growth Factor Receptor (EGFR) monoclonal antibody therapy in patients with metastatic colorectal cancer, and thus represent a true indicator of EGFR pathway activation status.Methodology/Principal Findings KRAS mutations were retrospectively studied using polymerase chain reactions and subsequent sequencing of codons 12 and 13 (exon 2) in 110 patients with metastatic colorectal tumors. These studies were performed using tissue samples from both the primary tumor and their related metastases (93 liver, 84%; 17 lung, 16%). All patients received adjuvant 5-Fluorouracil-based polychemotherapy after resection of metastases. None received anti-EGFR therapy. Mutations in KRAS were observed in 37 (34%) of primary tumors and in 40 (36%) of related metastases, yielding a 94% level of concordance (kappa index 0.86). Patients with primary tumors possessing KRAS mutations had a shorter disease-free survival period after metastasis resection (12.0 vs 18.0 months; P = 0.035) than those who did not. A higher percentage of KRAS mutations was detected in primary tumors of patiens with lung metastases than in patients with liver metastases (59% vs 32%; p = 0.054). To further evaluate this finding we analyzed 120 additional patients with unresectable metastatic colorectal cancer who previously had their primary tumors evaluated for KRAS mutational status for clinical purposes. Separately, the analysis of these 120 patients showed a tendency towards a higher degree of KRAS mutations in primary tumors of patients with lung metastases, although it did not reach statistical significance. Taken together the group of 230 patients showed that KRAS was mutated significantly more often in the primary tumors of patients with lung metastases (57% vs 35%; P = 0.006).Conclusions/SignificanceOur results suggest a role for KRAS mutations in the propensity of primary colorectal tumors to metastasize to the lung.

6007 Combining clinical factors with a genomic signature (ColoPrint) for the prognosis prediction of stage II and III colon cancer patients

This review discusses the role of molecular analysis in the diagnosis and treatment of gastrointestinal (GI) neoplasms. It is divided into 3 sections. The first section describes clinical applications of 11 immunohistochemical stains (p53, HER2, KIT, SDHB, SMAD4, beta-catenin, L-FABP, MLH1, PMS2, MSH2, and MSH6), the results of which directly reflect underlying genetic or epigenetic events. These applications are mainly diagnostic but in a few instances are predictive. Germline mutation testing is a diagnostic cornerstone in the hereditary cancer predisposition syndromes (HCPSs). Section two will describe the genotype and phenotype of 8 HCPSs presenting in the GI tract. Where available, guidelines based on evidence and/or expert opinion as to whom to test are presented. With our ever-expanding knowledge of the molecular genetic basis of cancer and an increasingly “biologic-oriented” therapeutic armamentarium, pathologists play a vital role in directing molecular-based predictive testing. The final section will discuss the 4 most mature examples in the GI tract: (1) HER2 testing to select patients with advanced gastroesophageal adenocarcinoma for anti-HER2 therapy, (2) KIT and PDGFRA mutation analysis to direct tyrosine kinase inhibitor therapy in gastrointestinal stromal tumor, (3) DNA mismatch repair function testing to determine the applicability of adjuvant chemotherapy in patients with stage II colorectal cancer (CRC), and (4) KRAS mutation analysis and related testing to determine the appropriateness of anti-EGFR monoclonal antibody therapy in patients with metastatic CRC.