MD Anderson Research Highlights for January 11, 2023

HOUSTON ― The University of Texas MD Anderson Cancer Center’s Research Highlights provides a glimpse into recent basic, translational and clinical cancer research from MD Anderson experts. Current advances include promising results for neoadjuvant immunotherapy in solid tumors with certain DNA repair defects, new therapeutic targets for treatment-resistant EGFR-mutant lung cancer, a deeper look at prognostic elements for core binding factor acute myeloid leukemia, a novel understanding of nuclear division inside polyploid giant cancer cells, a retrospective analysis showing benefit from triple combination therapy in recurrent neuroendocrine cervical cancer, a comprehensive molecular characterization of low-grade serous ovarian cancer, and benefits of targeted plus endocrine therapy across various subtypes of metastatic lobular breast cancer.

Neoadjuvant immunotherapy shows potential in MSI-H/dMMR solid tumors  The immune checkpoint inhibitor pembrolizumab significantly improves clinical outcomes in patients with advanced microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) solid tumors. Neoadjuvant, or presurgical, therapy has the potential to extend the benefits of immunotherapy earlier in the course of treatment and spare patients from surgical resection of affected organs. In a trial led by Kaysia Ludford, M.D., and Michael Overman, M.D., researchers evaluated neoadjuvant pembrolizumab in patients with localized resectable or high-risk resectable MSI-H/dMMR solid tumors. Among 33 evaluable patients, the best overall response rate was 82%. The pathological complete response rate was 65% in 17 patients who underwent surgery, and the remaining 18 patients continued pembrolizumab with a durable response. The findings demonstrate neoadjuvant pembrolizumab is safe and may be beneficial for patients with localized MSI-H/dMMR tumors, suggesting this treatment should be investigated further. Learn more in the Journal of Clinical Oncology

Targeting IL-6 could improve immunotherapy response in treatment-resistant lung cancer with EGFR mutations Patients with EGFR-mutant advanced non-small cell lung cancer (NSCLC) typically develop resistance to treatment with tyrosine kinase inhibitors (TKIs) targeting EGFR. Subsequent therapy with immune checkpoint inhibitors is ineffective, highlighting a need to understand mechanisms behind this resistance. IL-6 is an anti-inflammatory cytokine associated with poor outcomes in NSCLC, but its potential role in suppressing the anti-tumor immune response is unknown. In this study, researchers led by Sonia Patel, Ph.D., and John Heymach, M.D., Ph.D., investigated its role in the tumor microenvironment by using an IL-6 inhibitor in lab models of EGFR-mutant NSCLC. They discovered that tumors with resistance to EGFR TKIs upregulate IL-6, creating a microenvironment that suppresses the activity of natural killer (NK) cells and T cells. Inhibiting IL-6 improved the efficacy of immunotherapy, providing a potential target pathway to overcome TKI resistance in this subset of patients. Learn more in Clinical Cancer Research

Common kinase mutations do not impact responses to combination therapy in core binding factor-AML  
Core binding factor acute myeloid leukemia (CBF-AML) makes up 10-15% of all AML cases, and mutations in kinase signaling pathways previously have been associated with inferior survival. To better understand factors related to treatment outcomes, researchers led by Jayastu Senapati, M.D., and Gautam Borthakur, M.D., analyzed data from an ongoing Phase II trial evaluating fludarabine, cytarabine, and G-CSF (FLAG)-based treatment regimens – with idarubicin (IDA) or gemtuzumab ozogamicin (GO) – for patients with CBF-AML. At a median follow up of 92 months for 174 patients treated, the median relapse-free survival (RFS) was 148 months and median overall survival had not yet been reached. The researchers demonstrated the presence of FLT3, RAS and KIT kinase mutations did not negatively impact optimum molecular responses and survival with FLAG-based regimens. Patients with optimum molecular response during or after the consolidation therapy had an improved RFS. FLAG-GO led to higher frequency of optimal molecular response and improved RFS compared to FLAG-IDA. Further studies are needed to understand the appropriate therapy for patients who did not achieve optimal response from FLAG-based combinations. Learn more in the American Journal of Hematology. 

Time-lapse study reveals novel modes of nuclear division and cell formation for tumor development and immune resistance  Abnormal pathological features, such as a high nuclear to cytoplasmic (N/C) ratio and polyploid giant cancer cells (PGCCs), are associated with high-grade malignancy and often are used to make a cancer diagnosis. However, PGCCs traditionally have been considered “dead-end” cells due to their inability to divide by traditional mitosis, in which one cell becomes two. Challenging this common belief, Jinsong Liu, M.D., Ph.D., Xiaoran Li, Ph.D., and their team used long-term time-lapse imaging to characterize the nuclear dynamics and cell formation in patient-derived high-grade serous ovarian cancer 3D organoids. They found PGCCs can form via multiple novel modes of nuclear division, with or without mitosis. Additionally, the nuclei divided to form temporary new cells, known as fecundity cells, inside of a single giant cell. This process is similar to the growth and division modes seen in pre-embryogenesis. The nuclei of these cells can fuse or replicate within the giant cell, providing added physical barriers that prevent immune cell infiltration, increase treatment resistance and provide novel insights into tumor development. Learn more in Oncogene

Combination therapy improves progression-free survival in patients with recurrent neuroendocrine cervical cancer  Patients with recurrent neuroendocrine cervical cancer have a poor prognosis and limited treatment options. Previous studies show that a triple combination therapy of topotecan, paclitaxel and bevacizumab (TPB) is safe and effective in patients with squamous cell and adenocarcinoma cervical cancers. Researchers led by Michael Frumovitz, M.D., previously demonstrated that TPB improved median progression-free survival (PFS) in a small sample of women with recurrent neuroendocrine cervical cancer, and the regimen has since been incorporated as a viable treatment option. In this retrospective study, the researchers used data from the MD Anderson Neuroendocrine Cervical Tumor Registry (NeCTuR) to compare results from 62 patients receiving TPB for recurrence with those of 56 patients who received chemotherapy but not TPB. Patients treated with the TPB regimen had better median PFS than the non-TPB cohort (8.7 months versus 3.7 months) and a lower probability of disease progression (hazard ratio of .27 versus .87). Learn more in the American Journal of Obstetrics and Gynecology

Study offers comprehensive molecular profile of low-grade serous ovarian carcinoma   Low-grade serous ovarian cancer (LGSOC) mostly affects younger women and is resistant to chemotherapy, underscoring a need to identify more efficient treatment options. While KRAS/BRAF/NRAS mutations frequently are found in LGSOCs, little is known about other potential genetic aberrations involved in this disease. Researchers led by Kwong-Kwok Wong, Ph.D., performed a comprehensive molecular characterization of LGSOC samples to identify potential prognostic biomarkers and therapeutic targets. The researchers performed targeted sequencing of 409 cancer-related genes in 22 LGSOC and six serous borderline ovarian tumor samples, and they conducted whole-genome sequencing plus global proteomic and phosphoproteomic analyses of LGSOC samples from seven short-term and seven long-term survivors (defined as <40 and >60 months, respectively). This study discovered novel mutations and dysregulated proteins that are more prevalent in short-term survivors, highlighting several potential therapeutic targets. Learn more in the Journal of Translational Medicine.  

Targeted therapies show similar benefit for lobular breast cancer patients  Hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer patients have seen improved outcomes with the addition of targeted therapies to endocrine therapy. However, it is unknown whether patients with invasive lobular carcinoma (ILC) or mixed invasive ductal and lobular carcinoma (mixed) experience the same benefit from these therapies as those with invasive ductal carcinoma (IDC). Researchers led by Jason Mouabbi, M.D., conducted a retrospective study in patients with HR+/HER2− metastatic breast cancer to compare histology-based outcomes from the addition of CDK4/6 inhibitors, mTOR inhibitors or PI3K inhibitors to endocrine therapy. They analyzed progression-free survival (PFS) and overall survival (OS) in 2,975 patients using data from the MD Anderson prospectively collected breast cancer database. Adding targeted therapy to endocrine therapy did not result in statistically significant differences in PFS or OS duration among patients with IDC, ILC, and mixed histologies. These results provide reassurance that patients can receive similar benefit from these treatments, regardless of their histological subtype. Learn more in npj Breast Cancer. 

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