A Systems Biology Approach for Addressing Cisplatin Resistance in Non-Small Cell Lung Cancer.

Translational research in medicine, defined as the transfer of knowledge and discovery from the basic sciences to the clinic, is typically achieved through interactions between members across scientific disciplines to overcome the traditional silos within the community. Thus, translational medicine underscores 'Team Medicine', the partnership between basic science researchers and clinicians focused on addressing a specific goal in medicine. Here, we highlight this concept from a City of Hope perspective. Using cisplatin resistance in non-small cell lung cancer (NSCLC) as a paradigm, we describe how basic research scientists, clinical research scientists, and medical oncologists, in true 'Team Science' spirit, addressed cisplatin resistance in NSCLC and identified a previously approved compound that is able to alleviate cisplatin resistance in NSCLC. Furthermore, we discuss how a 'Team Medicine' approach can help to elucidate the mechanisms of innate and acquired resistance in NSCLC and develop alternative strategies to overcome drug resistance.

Pyramidal Decision Support Framework Leverages Subspecialty Expertise across Enterprise to Achieve Superior Cancer Outcomes and Personalized, Precision Care Plans.

The complexity of cancer care requires integrated and continuous support to deliver appropriate care. An expert network with complementary expertise and the capability of multidisciplinary care is an integral part of contemporary oncology care. Appropriate infrastructure is necessary to empower this network to deliver personalized precision care to their patients. Providing decision support as cancer care becomes exponentially more complex with new diagnostic and therapeutic choices remains challenging. City of Hope has developed a Pyramidal Decision Support Framework to address these challenges, which were exacerbated by the COVID pandemic, health plan restrictions, and growing geographic site diversity. Optimizing efficient and targeted decision support backed by multidisciplinary cancer expertise can improve individual patient treatment plans to achieve improved care and survival wherever patients are treated.

Addressing Drug Resistance in Cancer: A Team Medicine Approach.

Drug resistance remains one of the major impediments to treating cancer. Although many patients respond well initially, resistance to therapy typically ensues. Several confounding factors appear to contribute to this challenge. Here, we first discuss some of the challenges associated with drug resistance. We then discuss how a 'Team Medicine' approach, involving an interdisciplinary team of basic scientists working together with clinicians, has uncovered new therapeutic strategies. These strategies, referred to as intermittent or 'adaptive' therapy, which are based on eco-evolutionary principles, have met with remarkable success in potentially precluding or delaying the emergence of drug resistance in several cancers. Incorporating such treatment strategies into clinical protocols could potentially enhance the precision of delivering personalized medicine to patients. Furthermore, reaching out to patients in the network of hospitals affiliated with leading academic centers could help them benefit from such innovative treatment options. Finally, lowering the dose of the drug and its frequency (because of intermittent rather than continuous therapy) can also have a significant impact on lowering the toxicity and undesirable side effects of the drugs while lowering the financial burden carried by the patient and insurance providers.

Phase II Study Combining Pembrolizumab with Aromatase Inhibitor in Patients with Metastatic Hormone Receptor Positive Breast Cancer.

This study investigated the safety and antitumor activity of aromatase inhibitors (AI) with immune checkpoint inhibitor (ICI) pembrolizumab in patients with hormone receptor positive (HR+) human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC) in a phase II study with a safety lead-in (NCT02648477). Patients received pembrolizumab plus AI up to 2 years or until confirmed progression or unacceptable toxicity. Key eligibility criteria were HR+ HER2- MBC; RECIST v1.1 measurable disease; adequate organ function; and ECOG 0-1. Primary endpoints were safety and overall response rate. A 3-at-risk design was used for the safety lead-in with a targeted accrual of 20 patients. Grade 2 adverse events (AEs) included 35% fatigue, 20% rash, and 10% hot flashes. Grade 3 immune-related AEs (irAEs) related to pembrolizumab included 5% elevated AST/ALT, 5% rash, and 5% lymphopenia. Two (10%) patients had partial responses, three (15%) had stable disease, and 15 (75%) had progression of disease. Median progression-free survival was 1.8 months (95% CI 1.6, 2.6), median overall survival was 17.2 months (95% CI 9.4, NA), and median follow-up time was 40.1 months (range 31.3-46.8 months). The combination was well tolerated, but clinical activity was comparable to AI alone.

Hyperprogression on immunotherapy with complete response to chemotherapy in a NSCLC patient with high PD-L1 and STK11: A case report.

RATIONALE: Patients reporting high PD-L1 expression have shown to respond well to immunotherapy; however, some patients develop hyperprogressive disease upon initiation of immune checkpoint inhibitors. We report a patient with lung cancer and 100% PD-L1 expression who developed hyperprogressive disease while treated with pembrolizumab and responded well to salvage chemotherapy with carboplatin and pemetrexed. PATIENT CONCERNS: A 66-year-old African American female with 25-pack year smoking history, diabetes mellitus type 2, essential thrombocytosis, and a history of papillary thyroid carcinoma developed relapsed lung adenocarcinoma after 13 months of no evidence of disease. DIAGNOSIS: Surveillance imagine showed subcarinal and hilar lymphadenopathy, which was confirmed as recurrent lung adenocarcinoma via bronchoscopy. In addition, a brain scan showed a 5 mm enhancing left insular lesion. PD-L1 was reported as 100% expression. Staging was reported as stage IVB TxN3M1c lung adenocarcinoma. INTERVENTIONS: One fraction of radiation with a total dose of 20 Gray was delivered to the left insular lesion. The patient initiated pembrolizumab (200 mg) every 3 weeks. She was then treated with salvage chemotherapy consisting of carboplatin (AUC 5) and pemetrexed (500 mg/m) every 3 weeks for 3 cycles. OUTCOMES: The brain lesion resolved after the radiation therapy. The patient developed hyperprogression with a large pericardial effusion and right pleural effusion after 2 treatments of pembrolizumab. Her PD-L1 expression decreased from 100% to 0% over a 10-week period. Salvage chemotherapy with carboplatin and pemetrexed resulted with 20 months of ongoing to evidence of disease. LESSONS: Immune checkpoint inhibitor-related hyperprogressive disease may respond to second-line salvage chemotherapy. Complete PD-L1 expression loss was observed after the patient's treatment and could be a marker of hyperprogressive disease or tumor immunoevasion.

The Community Oncology and Academic Medical Center Alliance in the Age of Precision Medicine: Cancer Genetics and Genomics Considerations.

Recent public policy, governmental regulatory and economic trends have motivated the establishment and deepening of community health and academic medical center alliances. Accordingly, community oncology practices now deliver a significant portion of their oncology care in association with academic cancer centers. In the age of precision medicine, this alliance has acquired critical importance; novel advances in nucleic acid sequencing, the generation and analysis of immense data sets, the changing clinical landscape of hereditary cancer predisposition and ongoing discovery of novel, targeted therapies challenge community-based oncologists to deliver molecularly-informed health care. The active engagement of community oncology practices with academic partners helps with meeting these challenges; community/academic alliances result in improved cancer patient care and provider efficacy. Here, we review the community oncology and academic medical center alliance. We examine how practitioners may leverage academic center precision medicine-based cancer genetics and genomics programs to advance their patients' needs. We highlight a number of project initiatives at the City of Hope Comprehensive Cancer Center that seek to optimize community oncology and academic cancer center precision medicine interactions.

Non-Small Cell Lung Cancer from Genomics to Therapeutics: A Framework for Community Practice Integration to Arrive at Personalized Therapy Strategies.

Non-small cell lung cancer (NSCLC) is a heterogeneous disease, and therapeutic management has advanced with the identification of various key oncogenic mutations that promote lung cancer tumorigenesis. Subsequent studies have developed targeted therapies against these oncogenes in the hope of personalizing therapy based on the molecular genomics of the tumor. This review presents approved treatments against actionable mutations in NSCLC as well as promising targets and therapies. We also discuss the current status of molecular testing practices in community oncology sites that would help to direct oncologists in lung cancer decision-making. We propose a collaborative framework between community practice and academic sites that can help improve the utilization of personalized strategies in the community, through incorporation of increased testing rates, virtual molecular tumor boards, vendor-based oncology clinical pathways, and an academic-type singular electronic health record system.

Blastoid Variant Mantle Cell Lymphoma Expressing Aberrant CD3 and CD10 with Concurrent Small Lymphocytic Lymphoma: Establishment of a Clonal Relationship by B- and T-Cell Receptor Gene Rearrangements.

Mantle cell lymphoma (MCL) is an aggressive non-Hodgkin B-cell lymphoma typically expressing CD19, CD20, CD5, FMC-7, CyclinD1, and SOX-11 and harboring the IgH/CCND1 translocation. We report a blastoid variant of mantle cell lymphoma (MCL) involving an inguinal lymph node that, in addition to classical phenotypic and genetic findings, also aberrantly coexpresses surface CD10 and cytoplasmic CD3. Small lymphocytic lymphoma (SLL) was also present in the same lymph node and in the bone marrow. B- and T-cell gene rearrangement studies by PCR show the MCL and SLL to be clonally related. Expression of multiple aberrant antigens and concurrent lymphomas of different classifications can cause a diagnostic challenge. Awareness of such a presentation and integration of the data from morphologic evaluation, flow cytometry, immunohistochemistry, and FISH studies is required for proper diagnosis, prognosis, and therapy.

The microculture-kinetic (MiCK) assay: the role of a drug-induced apoptosis assay in drug development and clinical care.

A drug-induced apoptosis assay, termed the microculture-kinetic (MiCK) assay, has been developed. Blinded clinical trials have shown higher response rates and longer survival in groups of patients with acute myelocytic leukemia and epithelial ovarian cancer who have been treated with drugs that show high apoptosis in the MiCK assay. Unblinded clinical trials in multiple tumor types have shown that the assay will be used frequently by clinicians to determine treatment, and when used, results in higher response rates, longer times to relapse, and longer survivals. Model economic analyses suggest possible cost savings in clinical use based on increased generic drug use and single-agent substitution for combination therapies. Two initial studies with drugs in development are promising. The assay may help reduce costs and speed time to drug approval. Correlative studies with molecular biomarkers are planned. This assay may have a role both in personalized clinical therapy and in more efficient drug development.

Correlation of drug-induced apoptosis assay results with oncologist treatment decisions and patient response and survival.

BACKGROUND: An observational prospective nonblinded clinical trial was performed to determine the effect of a drug-induced apoptosis assay results on treatments planned by oncologists. METHODS: Purified cancer cells from patient biopsies were placed into the MiCK (Microculture Kinetic) assay, a short-term culture, which determined the effects of single drugs or combinations of drugs on tumor cell apoptosis. An oncologist received the assay results before finalizing the treatment plan. Use of the MiCK assay was evaluated and correlated with patient outcomes. RESULTS: Forty-four patients with successful MiCK assays from breast cancer (n = 16), nonsmall cell lung cancer (n = 6), non-Hodgkin lymphoma (n = 4), and others were evaluated. Four patients received adjuvant chemotherapy after MiCK, and 40 received palliative chemotherapy with a median line of therapy of 2. Oncologists used the MiCK assay to determine chemotherapy (users) in 28 (64%) and did not (nonusers) in 16 patients (36%). In users receiving palliative chemotherapy, complete plus partial response rate was 44%, compared with 6.7% in nonusers (P < .02). The median overall survival was 10.1 months in users versus 4.1 months in nonusers (P = .02). Relapse-free interval was 8.6 months in users versus 4.0 months in nonusers (P < .01). CONCLUSIONS: MiCK assay results are frequently used by oncologists. Outcomes appear to be statistically superior when oncologists use chemotherapy based on MiCK assay results compared with when they do not use the assay results. When available to oncologists, MiCK assay results help to determine patient treatment plans.

A copay foundation assistance support program for patients receiving intravenous cancer therapy.

PURPOSE: With the advent of newer cancer therapies (eg, biologic and cytotoxic), treatment is becoming increasingly expensive for patients with cancer. Patients enrolled in Medicare and commercial insurance plans often have large copay requirements with each treatment cycle. Often, these patients undergo significant financial hardship, and some patients decline treatment. We have developed a support program that works closely with all copay assistance foundations to secure financial assistance to facilitate appropriate treatment. METHODS: In September, 2008 we initiated a coordinated program with various copay assistance foundations, including Healthwell, Cancer Care, Patient Access, Chronic Disease Fund, Beckstrand Cancer, Lilly Cares and the Leukemia and Lymphoma Society. Patients requesting assistance with chemotherapy copay were enrolled in this program. Information about income level, chemotherapy regimens, and associated copay was given to these foundations, who then determined the amount of monetary assistance. RESULTS: Since the initiation of this program, of 201 patients who began receiving chemotherapy, 25 (12.4%) requested assistance with this program for either intravenous or oral treatments. The current results of time delays for foundation decision, success rates and administrative costs to secure funding will be presented at the time of the poster presentation. CONCLUSION: Copay for chemotherapy drugs is a financial hardship for a significant number of patients. Coordinated resources must be provided and reimbursed to facilitate appropriate and sustainable cancer care. This program is a successful model for other centers to adopt.