Hodgkin lymphoma: targeting the tumor microenvironment as a therapeutic strategy.

Over the past decade, new biologic insights have revealed the key role of the tumor microenvironment in the pathogenesis of classical Hodgkin lymphoma (cHL). The primary Hodgkin Reed-Sternberg (HRS) tumor cells normally constitute less than 1% of the tumor cellularity in cHL, and are surrounded by an abundant and heterogeneous inflammatory infiltrate. The cross talk between the HRS cells and the cells of the cHL microenvironment sustains tumor growth and survival. An improved understanding of this phenomenon has led to the development of novel antitumor strategies that alter the cHL microenvironment, changing it from protective to cytotoxic. Developing new strategies remains a high priority because--despite the curability of cHL--as many as one-third of advanced-stage patients will relapse after first-line therapy. Furthermore, only half of relapsed patients will obtain long-term disease control through autologous stem cell transplant. In this review, we will provide an overview of the role of the cHL microenvironment in disease biology, the agents currently available or under investigation targeting the cHL microenvironment, and the most promising and innovative treatment platforms being evaluated in clinical trials.

Mantle cell lymphoma in relapse: the role of emerging new drugs.

PURPOSE OF REVIEW: Despite current advances in the therapy for newly diagnosed mantle cell lymphoma (MCL), relapsed MCL continues to have a poor prognosis. Advances in our understanding of the molecular pathogenesis of MCL are yielding many promising novel therapies. RECENT FINDINGS: This article reviews the unique biology of MCL and describes how our understanding of its cell cycle dysregulation, and impaired apoptotic pathways is yielding many potential therapeutic targets including cyclin D1 and the cell cycle regulatory proteins, inhibitors of mammalian target of rapamycin, the proteasome, and proapoptotic family members. Recent preclinical and clinical data with cdk inhibitors, histone deacetylase inhibitors, the proteasome inhibitor bortezomib, mammalian target of rapamycin inhibitors, and other experimental strategies such as immunotherapy and microRNA are discussed. SUMMARY: Understanding these targeted therapies in the context of the biology of MCL, has the potential to develop novel therapeutic platforms for the treatment of relapsed MCL, and will hopefully change the outcome for patients with this challenging clinical condition.

Clinical Cancer Advances 2020: Annual Report on Progress Against Cancer From the American Society of Clinical Oncology.

A MESSAGE FROM ASCO'S PRESIDENT: Shortly before I was elected President of ASCO, I attended the 65th birthday party of a current patient. She had been diagnosed 10 years earlier with metastatic breast cancer and hadn't been sure she wanted to move forward with further treatment. With encouragement, she elected to participate in a clinical trial of an investigational drug that is now widely used to treat breast cancer. Happily, here we were, celebrating with her now-married daughters, their husbands, and three beautiful grandchildren, ages 2, 4, and 8. Such is the importance of clinical trials and promising new therapies.Clinical research is about saving and improving the lives of individuals with cancer. It's a continuing story that builds on the efforts of untold numbers of researchers, clinicians, caregivers, and patients. ASCO's Clinical Cancer Advances report tells part of this story, sharing the most transformative research of the past year. The report also includes our latest thinking on the most urgent research priorities in oncology.ASCO's 2020 Advance of the Year-Refinement of Surgical Treatment of Cancer-highlights how progress drives more progress. Surgery has played a fundamental role in cancer treatment. It was the only treatment available for many cancers until the advent of radiation and chemotherapy. The explosion in systemic therapies since then has resulted in significant changes to when and how surgery is performed to treat cancer. In this report, we explore how treatment successes have led to less invasive approaches for advanced melanoma, reduced the need for surgery in renal cell carcinoma, and increased the number of patients with pancreatic cancer who can undergo surgery.Many research advances are made possible by federal funding. With the number of new US cancer cases set to rise by roughly a third over the next decade, continued investment in research at the national level is crucial to continuing critical progress in the prevention, screening, diagnosis, and treatment of cancer.While clinical research has translated to longer survival and better quality of life for many patients with cancer, we can't rest on our laurels. With ASCO's Research Priorities to Accelerate Progress Against Cancer, introduced last year and updated this year, we've identified the critical gaps in cancer prevention and care that we believe to be most pressing. These priorities are intended to guide the direction of research and speed progress.Of course, the effectiveness or number of new treatments is meaningless if patients don't have access to them. High-quality cancer care, including clinical trials, is out of reach for too many patients. Creating an infrastructure to support patients is a critical part of the equation, as is creating connections between clinical practices and research programs. We have much work to do before everyone with cancer has equal access to the best treatments and the opportunity to participate in research. I know that ASCO and the cancer community are up for this challenge.Sincerely,Howard A. "Skip" Burris III, MD, FACP, FASCOASCO President, 2019-2020.

Safety and immunogenicity study of NY-ESO-1b peptide and montanide ISA-51 vaccination of patients with epithelial ovarian cancer in high-risk first remission.

PURPOSE: The cancer-testis antigen NY-ESO-1 is expressed by >40% of advanced epithelial ovarian cancers and is a promising immunotherapeutic target. In this study, we describe the effects of vaccination with the HLA-A*0201-restricted NY-ESO-1b peptide on patients with epithelial ovarian cancer in high-risk first remission. EXPERIMENTAL DESIGN: After primary surgery and chemotherapy, high-risk epithelial ovarian cancer patients in first clinical remission received NY-ESO-1b peptide and Montanide every 3 weeks for five vaccinations. Tumor expression was evaluated by immunohistochemistry. Toxicity was monitored using National Cancer Institute Common Toxicity Criteria Scale Version 2. NY-ESO-1 specific humoral immunity (ELISA), T-cell immunity (tetramer and ELISPOT), and delayed-type hypersensitivity were assessed on weeks 0, 1, 4, 7, 10, 13, and 16. RESULTS: Treatment-related adverse events included grade 1 fatigue, anemia, pruritus, myalgias, and hyperthyroidism and grade 2 hypothyroidism. There were no grade 3/grade 4 adverse events. Three of four patients (75%) with NY-ESO-1-positive tumor showed T-cell immunity by tetramer (0.6-9.5%) and ELISPOT (range, 35-260 spots). Four of five patients (80%) with NY-ESO-1-negative tumor showed T-cell immunity by tetramer (1.0-12.1%) and/or ELISPOT (range, 35-400 spots). With a median follow-up of 11.3 months, six of nine patients (67%) have recurred, with a median progression-free survival of 13 months (95% confidence interval, 11.2 months-not reached). Three of nine patients remain in complete clinical remission at 25, 38, and 52 months. CONCLUSION: Vaccination of high-risk HLA-A*0201-positive epithelial ovarian cancer patients with NY-ESO-1b and Montanide has minimal toxicity and induces specific T-cell immunity in patients with both NY-ESO-1-positive and NY-ESO-1-negative tumors. Additional study is warranted.

Targeting CD30 in hodgkin lymphoma: antibody-drug conjugates make a difference.

CD30 expression is characteristic of the malignant Reed-Sternberg cell in Hodgkin lymphoma (HL) and several other lymphoid malignancies, such as anaplastic large-cell lymphoma (ALCL). Although unconjugated anti-CD30 antibodies have had minimal therapeutic activity in patients with HL as single agents, the CD30-directed antibody-drug conjugate (ADC) brentuximab vedotin has demonstrated activity that has resulted in its recent regulatory approval for the treatment of patients with relapsed HL and ALCL. Approximately 75% of patients with recurrent HL achieve objective responses, with the principal toxicity being peripheral neuropathy. Ongoing studies are evaluating treatment with this agent as part of first-line therapy, for patients with relapsed disease, and for patients with resistant disease and limited other options. Brentuximab vedotin demonstrates the therapeutic value of antibody-drug conjugation and serves as a model of how a novel, targeted approach can be employed to potentially further improve outcomes in settings where curative chemotherapeutic regimens are already available.

Preoperative serum YKL-40 is a marker for detection and prognosis of endometrial cancer.

OBJECTIVE: YKL-40 is a secreted glycoprotein of the chitinase family that has been previously described as a diagnostic and prognostic marker for a number of cancers, including epithelial ovarian cancer. In this study, we examined the frequency of serum elevation as well as the diagnostic and prognostic significance of this serum marker in endometrial cancer. MATERIALS AND METHODS: Preoperative serum levels of YKL-40 and CA125 were evaluated by enzyme-linked immunosorbent assay (ELISA) for all endometrial cancer patient samples (34) available in the Memorial Sloan-Kettering Cancer Center Gynecology Service Tissue Bank between the years 1987 and 2002, and compared to a cohort of normal individuals. A YKL-40 value of 61 ng/mL has previously been determined to represent the upper limit of normal. YKL-40 values were correlated with clinical characteristics, including patient age, tumor grade, histology, clinical stage, and clinical outcome (progression-free survival [PFS] and overall survival [OS]). RESULTS: YKL-40 was elevated (>61 ng/mL) in 26 (76%) of 34 endometrial cancer patients compared with elevations of CA125 in 21 (62%) of 34 patients (P=0.09). Twenty-eight (82%) of all 34 patients had elevations of either CA125 or YKL-40 or both; 16 (89%) of 18 advanced-stage endometrial cancer patients had elevation of at least one of these two markers. Median preoperative YKL-40 value was 137 ng/mL (range, 22-1738 ng/mL) for endometrial cancer patients compared with 28 ng/mL (range, 15-72 ng/mL) for normal healthy subjects (P<0.0001). There was no statistically significant association of YKL-40 with patient age, tumor grade, histology, or stage. Elevation of YKL-40 (>80 ng/mL) was correlated with poor clinical outcome in univariate analysis, but was not demonstrated in multivariate analysis. At 5 years' follow-up, the PFS rate was 80% for patients with YKL-40<80 ng/mL compared with 43% for patients with YKL-40>80 ng/mL (P=0.004). The 5-year OS rate for patients with YKL-40<80 ng/mL was 79% compared with 48% for patients with YKL-40>80 ng/mL (P=0.047). CONCLUSION: Preoperative serum YKL-40 is frequently elevated and may represent a novel marker for the detection of endometrial cancer and the identification of high-risk subsets of patients with worse clinical outcome. Further investigation of this promising endometrial cancer marker in larger studies is warranted.

Lysophosphatidic acid acyltransferase-beta (LPAAT-beta) is highly expressed in advanced ovarian cancer and is associated with aggressive histology and poor survival.

BACKGROUND: Lysophosphatidic acid acyltransferase-beta (LPAAT-beta) tumor expression is an emerging prognostic, diagnostic, and therapeutic target in early epithelial ovarian cancer (EOC). The significance of tumor overexpression of LPAAT-beta was investigated in a large number of advanced- and early-stage EOC patients. METHODS: LPAAT-beta expression was analyzed by immunohistochemistry (IHC) in 158 ovarian tumors, including 68 advanced and 90 low-stage tumors, representing all grades and histologies (including 33 borderline tumors). In advanced-stage patients, tissue from multiple sites was evaluated to assess differential expression of LPAAT-beta in local tumor and distant metastases. RESULTS: LPAAT-beta was overexpressed in 90 (57%) of all 158 ovarian tumors. Forty-nine (72%) of 68 advanced tumors overexpressed LPAAT-beta. LPAAT-beta was associated with the presence of carcinoma versus borderline histology (67% vs. 18%, P < .0001), high histologic grade [according to the Silverberg Grading Scheme] (Grade 1, 25%; Grade 2, 21%; and Grade 3, 54%; P < .0001), and with papillary-serous histology. In an analysis of the 125 carcinoma patients, LPAAT-beta increased with but was not significantly associated with advanced clinical stage (P = .1431). LPAAT-beta expression was associated with shortened progression-free survival (PFS) (5-year PFS, 32% for LPAAT-beta-positive vs. 60% for LPAAT-beta-negative; P = .0318) and decreased overall survival (OS) (5-year OS, 54% for LPAAT-beta-positive vs. 74% for LPAAT-beta-negative; P = .0173). CONCLUSIONS: LPAAT-beta is highly expressed in advanced ovarian tumors and is associated with aggressive histology and decreased PFS and OS. LPAAT-beta is an intriguing prognostic tool for the identification of high-risk EOC and a potential target for directed therapy that warrants further study.