Antagonists of the Mu-Opioid Receptor in the Cancer Patient: Fact or Fiction?

Current Oncology Reports - Antagonists of mu-opioid receptor role in cancer progression remains to be elucidated. The objective of this review was to summarize the available evidence on antagonists...     

Extending Outcomes: Epidermal Growth Factor Receptor–Targeted Monoclonal Antibodies in Non–Small-Cell Lung Cancer

The epidermal growth factor receptor (EGFR) pathway plays an important part in the formation of many epithelial malignancies and has been the target of intensive drug development. Although the small-molecule EGFR tyrosine kinase inhibitors (TKIs) have an established role as single-agent therapy in the second- or third-line treatment of patients with advanced Non—Small-cell lung cancer (NSCLC), they have failed to demonstrate any additive benefit when combined with standard cytotoxic chemotherapy. Monoclonal antibodies (MoAbs) to EGFR are a distinct class of agents that differ significantly from the TKIs in their interaction with the EGFR pathway. A number of MoAbs targeting EGFR are currently in development and their clinical usefulness in the treatment of NSCLC is discussed, with particular attention given to cetuximab.     

Prognostic Role of Receptor Tyrosine Kinase–Like Orphan Receptors in Intestinal-Type Gastric Cancer

Background: Gastric cancer (GC) is diagnosed at advanced stages and has high mortality rates. Surgical resection and adjuvant chemotherapy are the main therapeutic approaches for GC. Despite curative resection, recurrence and metastasis contribute to a high mortality rate in patients with GC. The receptor-tyrosine-kinase-like orphan receptors 1/2 (ROR1/2) are transmembrane proteins belonging to the receptor tyrosine kinase (RTK) family. ROR1 and ROR2 are known to overexpress in the tumor tissues from several types of cancer patients. However, the role of RORs in the prognosis has not been understood. Methods: This study aimed to determine the association of mRNA expression of ROR1, ROR2, and their signaling components WNT5A, NKX2-1, and FOXF1, with the survival outcome of GC patients. We performed Kaplan-Meir survival analysis on publicly available ‘The Cancer Genome Atlas (TCGA)’ data sets using ‘Kaplan-Meir Plotter.’ Results: High mRNA expression of ROR1, ROR2, NKX2-1, and FOXF1 was significantly correlated with worse overall survival (OS) of GC patients. Interestingly ROR1 and ROR showed a prognostic role in the intestinal subtype, but not in the diffuse subtype of GC.  Furthermore, ROR1 was positively correlated with regulatory T cells and M2-type macrophages and negatively correlated with Th17 and natural killer T cells in the tumor stroma of patients with GC. Conclusion: We conclude that the expression of ROR1, ROR2, and their associated genes correlate with worst prognosis of GC patients, particularly in the intestinal type.     

Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitors in Non–Small-Cell Lung Cancer

Angiogenesis is essential for cancer growth and progression. Vascular endothelial growth factor (VEGF) plays a crucial role in angiogenesis. The addition of bevacizumab, an antibody to vascular endothelial growth factor (VEGF), to paclitaxel and carboplatin improves survival compared with chemotherapy alone in patients with previously untreated metastatic nonsquamous non–small-cell lung cancer (NSCLC). Vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR TKIs) are a new class of drugs that target the TK domain of the VEGF receptors. To evaluate the role of this class of agents in the treatment of NSCLC, some phase II and phase III studies using these agents alone or in combination with other agents have been completed. This review summarizes the currently available data on VEGFR TKIs in the treatment of NSCLC.     

Pilot Trial of Preoperative (Neoadjuvant) Letrozole in Combination With Bevacizumab in Postmenopausal Women With Newly Diagnosed Estrogen Receptor— or Progesterone Receptor—Positive Breast Cancer

IntroductionTumor content or expression of vascular endothelial growth factor (VEGF) is associated with impaired efficacy of antiestrogen adjuvant therapy. We designed a pilot study to assess the feasibility and short-term efficacy of neoadjuvant letrozole and bevacizumab (anti-VEGF) in postmenopausal women with stage II and III estrogen receptor/progesterone receptor—positive breast cancer.Patients and MethodsPatients were treated with a neoadjuvant regimen of letrozole orally 2.5 mg/day and bevacizumab intravenously 15 mg/kg every 3 weeks for a total of 24 weeks before the surgical treatment of their breast cancer. Patients were followed for toxicity at 3-week intervals, and tumor assessment (a physical examination and ultrasound) was performed at 6-week intervals. Positron emission tomography (PET) scans were performed before therapy and 6 weeks after the initiation of therapy.ResultsTwenty-five evaluable patients were treated. The regimen was well-tolerated, except in 2 patients who were taken off the study for difficulties controlling their hypertension. An objective clinical response occurred in 17 of 25 patients (68%), including 16% complete responses (CRs) and 52% partial responses. The 4 patients with clinical CRs manifested pathologic CRs in their breasts (16%), although 1 patient had residual tumor cells in her axillary nodes. Eight of 25 patients (32%) attained stage 0 or 1 status. The PET scan response at 6 weeks correlated with clinical CRs and breast pathologic CRs at 24 weeks (P < .0036).ConclusionCombination neoadjuvant therapy with letrozole and bevacizumab was well-tolerated and resulted in impressive clinical and pathologic responses. The Translational Breast Cancer Research Consortium has an ongoing randomized phase II trial of this regimen in this patient population.     

Acquired Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non–Small-Cell Lung Cancers Dependent on the Epidermal Growth Factor Receptor Pathway

Most advanced Non–Small-cell lung cancers (NSCLCs) with activating epidermal growth factor receptor (EGFR) mutations (exon 19 deletions or L858R) initially respond to the EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib. However, over time (median of 6–12 months), most tumors develop acquired resistance to EGFR TKIs. Intense research in these NSCLCs has identified two major mechanisms of resistance to gefitinib/erlotinib: secondary resistance mutations and “oncogene kinase switch" systems. The secondary T790M mutation occurs in 50% of EGFR-mutated patients with TKI resistance, and in vitro, this mutation negates the hypersensitivity of activating EGFR mutations. Sensitive detection methods have identified a proportion of TKI-naive tumors that carry T790M, and these resistant clones may be selected after exposure to gefitinib or erlotinib. Other secondary resistance mutations (D761Y, L747S, T854A) seem to be rare. The amplification of the MET oncogene is present in 20% of TKI-resistant tumors; however, in half of the cases with this “oncogene kinase switch" mechanism the T790M is coexistent. It is possible that other kinases (such as insulin-like growth factor-1 receptor [IGF-1R]) might also be selected to bypass EGFR pathways in resistant tumors. The growing preclinical data in EGFR-mutated NSCLCs with acquired resistance to gefitinib or erlotinib has spawned the initiation or conception of clinical trials testing novel EGFR inhibitors that in vitro inhibit T790M (neratinib, XL647, BIBW 2992, and PF-00299804), MET, or IGF-1R inhibitors in combination with EGFR TKIs, and heat shock protein 90 inhibitors. Ongoing preclinical and clinical research in EGFR-mutated NSCLC has the potential to significantly improve the outcomes of patients with these somatic mutations.     

Inducing or Preventing Subsequent Malignancies for Breast Cancer Survivors? Double-edged Sword of Estrogen Receptor and Progesterone Receptor

Introduction

Hormone receptor and human epidermal growth factor receptor 2 (HER2) status is important for breast cancer (BC) treatment. Previous studies have shown that the long-term treatment outcomes of BC are significantly impaired by the development of subsequent malignancies. Therefore, in the present study, we evaluated the effect of hormone receptor/HER2 status on subsequent malignancies in breast cancer survivors.

Efficacy of Palbociclib Combinations in Hormone Receptor–Positive Metastatic Breast Cancer Patients After Prior Everolimus Treatment

Purpose

Outcome data on hormone receptor positive (HR⁺), human epidermal growth factor receptor 2 (HER2) nonamplified (HER2^?) metastatic breast cancer (MBC) treated with palbociclib after treatment with everolimus are lacking. The PALOMA-3 trial, showing benefit of palbociclib plus fulvestrant compared to fulvestrant alone in HR⁺HER2^? MBC after progression while receiving endocrine therapy excluded women previously treated with everolimus. The objective of this study was to examine outcomes of HR⁺HER2^? MBC with prior exposure to everolimus while receiving palbociclib-based therapy.

Update on Estrogen Receptor–Positive Breast Cancer Risk Reduction

Women who are at increased risk of breast cancer can be identified using individual risk factors or by using validated quantitative risk assessment models. There are millions of such women in the US population alone, and many additional millions of women at increased risk worldwide. Decades of randomized, prospective studies of these women using selective estrogen receptor modulators (SERMs) have shown that risk can be reduced safely and effectively by 50% for all invasive breast cancer and by nearly 70% or more for estrogen receptor–positive breast cancer. Safety and tolerability of the SERMs are acceptable in the published studies, and two SERMs, tamoxifen and raloxifene, are approved by the US Food and Drug Administration for breast cancer risk reduction. Nevertheless, the drugs are not widely used despite reasonable cost per year of life saved (or morbidity avoided). Clinicians must endeavor to identify women who are suitable candidates for these drugs and educate them about their safety and utility.     

Epidermal Growth Factor Receptor Mutation Status and Adjuvant Chemotherapy in Resected Advanced Non–Small-Cell Lung Cancer

IntroductionThis study was to assess the association of epidermal growth factor receptor (EGFR) mutation status and efficacy of adjuvant chemotherapy in patients with fully resected IIIA-N2 non–small-cell lung cancer (NSCLC).Materials and MethodsTumor samples (n = 150) from patients with IIIA-N2 NSCLC who either had or had not received paclitaxel plus carboplatin or vinorelbine plus carboplatin doublet adjuvant chemotherapy were analyzed for EGFR mutations. The association of the presence of EGFR mutations and survival was assessed.ResultsMutations were identified in 43 (28.7%) patients (n = 25 in the no chemotherapy [observation] arm and n = 18 in the chemotherapy arm). Patients with EGFR mutations had statistically significant improved disease-free survival (41 months [95% CI, 25.1-56.9 months] vs. 20 months [95% CI, 15.0-25.0 months]; 2P = .005) and overall survival (50 months [95% CI, 37.6-62.4 months] vs. 25 months [95% CI, 20.8-29.2 months]; 2P = .001), regardless of treatment. The patients with wild-type EGFR had greater overall survival with chemotherapy compared with no adjuvant therapy (hazard ratio [HR] 4.748 [95% CI, 2.844-7.928]; 2P < .001). In contrast, in patients with EGFR mutation in the observation group compared with the chemotherapy group had longer median disease-free survival (49 months [95% CI, 35.1-62.9 months] for the observation arm vs. 30 months [95% CI, 23.8-36.2 months] for the chemotherapy arm, 2P = .195) and overall survival (59 months [95% CI, 43.9-74.1 months] vs. 33 months [95% CI, 24.7-41.3 months]; 2P = .050).ConclusionsIn this exploratory study, the status of EGFR mutations was associated with different clinical outcomes in patients with resected IIIA-N2 NSCLC. Further studies are required to confirm that a patient's adjuvant treatment may be customized to their EGFR mutational status.     

Phase 2 Study of Erlotinib in Combination With Linsitinib (OSI-906) or Placebo in Chemotherapy-Naive Patients With Non–Small-Cell Lung Cancer and Activating Epidermal Growth Factor Receptor Mutations

Introduction

First-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor treatment of advanced non–small-cell lung cancer with EGFR-activating mutations improves outcomes compared with chemotherapy, but resistance develops in most patients. Compensatory signaling through type 1 insulin-like growth factor 1 receptor (IGF-1R) may contribute to resistance; dual blockade of IGF-1R and EGFR may improve outcomes.

The Role of Anti–Epidermal Growth Factor Receptor and Anti–Vascular Endothelial Growth Factor Therapies in the Treatment of Non–Small-Cell Lung Cancer

Standard first-line therapy for non–small-cell lung cancer (NSCLC) with platinum-based agents, given in combination with cytotoxic compounds, has reached a relative plateau in its therapeutic efficacy. Novel molecular targeted agents acting on specific pathways have emerged as effective agents for treating NSCLC; some have already produced positive results in phase III trials. Notably, inhibition of the vascular endothelial growth factor (VEGF) pathway with an anti-VEGF antibody, bevacizumab, and targeting the epidermal growth factor receptor (EGFR) pathway with a small-molecule EGFR tyrosine kinase inhibitor erlotinib or a monoclonal antibody (cetuximab) have demonstrated prolonged survival in patients with advanced disease in both the first- and second-line settings. The heterogeneity of signaling processes leading to tumor cell survival and proliferation supports the targeting of multiple signaling pathways as an effective anticancer treatment strategy. Consequently, rational combinations of molecular targeted agents might offer superior clinical efficacy and an alternative treatment option to patients refractory to, or unable to tolerate, standard chemotherapy. The challenge lies in determining which molecular entities should be pursued and the best approach to combine them. This review discusses the potential clinical utility of combining bevacizumab and erlotinib to inhibit both angiogenesis and EGFR signaling as a valid nonchemotherapeutic approach for the treatment of NSCLC. Other combinations of novel therapies that block EGFR and angiogenic pathways, as well as complementary signaling pathways, with unique modes of action and low toxicity profiles could offer an increased repertoire of individualized treatment options for patients with advanced NSCLC.     

Recent Advances in the Use of Chimeric Antigen Receptor–Expressing T-Cell Therapies for Treatment of Multiple Myeloma

Introduction: Chimeric antigen receptor T cell (CAR-T) therapies have revolutionized the treatment paradigm for heavily pretreated B-cell malignancies such as large B-cell lymphoma. There is a major unmet need for effective treatments for heavily pretreated relapsed/refractory multiple myeloma (RRMM), for which many CAR-T therapies are under active clinical investigation.Goal of the review: This review provides an overview of recently updated clinical trial data and indirect treatment comparison analyses regarding two clinically advanced CAR-T therapies, idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel).Discussion: Recently presented data after prolonged follow-up periods for ide-cel (KarMMa) and cilta-cel (CARTITUDE-1) have demonstrated that both therapies have the potential to elicit responses in individuals with heavily pretreated RRMM. Indirect treatment comparisons between cilta-cel and ide-cel suggest cilta-cel is associated with deeper and more durable responses than ide-cel in triple class-exposed RRMM; however, these types of comparisons have limitations and direct head-to-head trials are needed to confirm these findings. Additional indirect treatment comparisons conducted separately for ide-cel and cilta-cel have demonstrated that these CAR-T therapies hold promise for substantial clinical benefit relative to currently available treatments for RRMM. Further considerations, including safety profiles and real-world treatment considerations, are also discussed.Conclusion: Data collected to date support CAR-T therapies holding substantial promise for patients with heavily pretreated RRMM relative to other currently available therapies. Additional real-world data will help provide further insights into the comparative efficacy and safety profiles of these treatments in RRMM as these treatments become more widely available.     

Estrogen Receptor β Expression and Its Clinical Implication in Breast Cancers: Favorable or Unfavorable?

There are two estrogen receptor (ER) genes (ESR1/ERα and ESR2/ERβ) in humans. Of those. ERβ, the second ER isotype identified in 1996, is differentially expressed in different phenotypes and molecular subtypes of breast cancer (BCa), and is highly expressed in ERα-negative BCa and triple-negative BCa (TNBC). This review summarizes the potential clinical relevance of ERβ in BCa and the challenges associated with studies on the role of ERβ in BCa. The experimental and clinical studies evaluating clinical outcomes and associations with clinical characteristics and responses to endocrine therapy on targeting ERβ reviewed herein indicate that ERβ is a clinically important biomarker in BCa. The reviewed studies also suggest that each ERβ isoform has a distinct role in BCa subtypes and the potential of novel- targeted therapies in BCa, especially ERα-negative BCa and TNBC. However, the findings of many studies on ERβ are inconsistent, and the exact role of ERβ in BCa remains elusive; this may potentially be attributed to the complexity of ERβ isoforms, but also to the lack of standardized testing protocol. Thus, successful clinical application of ERβ requires the development of standardized, reproducible, and objective measurement methods for ERβ that can be widely and routinely applied in clinical setting.