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Given the abundance of new research, it can be challenging to stay current on the latest advancements and findings. Oncology Times is here to help with summaries of the newest studies to ensure you are up-to-date on the latest innovations in oncology practice.



Mutation patterns identify adult patients with de novo acute myeloid leukemia aged 60 years or older who respond favorably to standard chemotherapy: an analysis of Alliance studies

A new study has identified combinations of gene mutations that predict whether an older person with acute myeloid leukemia (AML) might achieve complete remission when treated with standard chemotherapy (Leukemia 2018; doi:10.1038/s41375-018-0068-2). The AML cells of 423 patients aged 60 and older for mutations in 80 cancer- or leukemia-associated genes were analyzed. Researchers then used that mutation information to classify the patients into groups that had a good, poor, or intermediate outcome after treatment with standard chemotherapy. Overall the study, according to researchers, highlighted the extremely poor outcome of AML patients aged 60 years and older with current treatment approaches. However, investigators found specific mutation combinations that associated with patient survival. Of patients in the good-risk group, 82 percent experienced relapse of their disease, as did patients in the intermediate-risk group. Data showed that the "good risk" group of patients was not only driven by the beneficial influence of NPM1 mutations, but was additionally altered by coexisting mutations in other genes. "Mutation testing is important for the identification of the small group of older patients who have an excellent chance to achieve a complete remission when treated with standard induction chemotherapy," according to the findings.



Chemoresistance evolution in triple-negative breast cancer delineated by single-cell sequencing

New findings suggest breast cancer cell resistance to chemotherapy may be pre-existing and the cells may even adapt to become resistant when confronted by the chemotherapy itself (Cell 2018; doi:10.1016/j.cell.2018.03.041). Researchers analyzed 20 triple-negative breast cancer patients treated with neoadjuvant chemotherapy. The team looked at genetic changes by sequencing the coding regions of genes across the genome. Investigators sought to understand whether new genetic mutations occurring after chemotherapy erupted spontaneously due to acquired resistance, or whether the mutations already existed at very low levels prior to treatment. Utilizing single-cell DNA and RNA sequencing, researchers performed an analysis of eight clonal persistent patients, measuring miniscule portions of DNA and RNA, and found responses to neoadjuvant chemotherapy were pre-existing and, therefore, adaptively selected. However, the expression of resistant genes was acquired by subsequent reprogramming as a result of chemotherapy. "Our data showed that resistant genotypes were pre-existing and adaptively selected by neoadjuvant chemotherapy, while transcriptional profiles were acquired by reprogramming in response to chemotherapy in triple-negative breast cancer patients," study authors concluded.



A PET imaging agent for evaluating PARP-1 expression in ovarian cancer

Utilizing CRISPR/Cas9 gene editing technology, researchers isolated a key genetic feature that could cause resistance to PARP inhibitors in patients with ovarian cancer (J Clin Invest 2018; doi:10.1172/JCI97992). Investigators found that PARP inhibitors specifically require the presence of PARP-1 in order to take effect. Additionally, the findings showed that a radioactive tracer developed at Penn Medicine makes PARP-1 visible during PET scans and may provide a method of measuring PARP-1 in ovarian cancer that complements biopsy. CRISPR/Cas9 gene editing was used in the lab to delete PARP-1 from ovarian cancer cells, then exposed those cells to PARP inhibitors and compared them to a control group with PARP-1. Cells without PARP-1 showed less DNA damage and less responsiveness to the inhibitors than the unedited control group cells, according to researchers. They used a radioactive tracer that binds to PARP-1, making it visible during PET scans. After a pre-clinical test using mouse models showed the tracer was hitting its specific molecular target, the study's authors moved to a phase I trial. A clinical trial involving 10 patients led to 13 tissue samples. These samples had a wide spectrum of uptake of the tracer, but that uptake correlated with PARP-1 expression. "This work confirms the translational potential of a PARP-1 PET imaging agent and supports future clinical trials to test PARP-1 expression as a method to stratify patients for PARP inhibitor therapy," study authors wrote.



Assessment of tumor sequencing as a replacement for Lynch syndrome screening and current molecular tests for patients with colorectal cancer

Recently published data suggest a single, upfront genomic test is more effective for detecting Lynch syndrome in colorectal cancer (CRC) patients than the traditional multiple, sequential testing approach (JAMA Oncol 2018; doi:10.1001/jamaoncol.2018.0104). In an effort to determine whether up-front tumor sequencing could replace the current multiple sequential test approach, researchers analyzed tumor samples from 419 CRC patients who participated in the Ohio Colorectal Cancer Prevention Initiative (OCCPI), a statewide research study to screen newly diagnosed CRC patients and their biological relatives for Lynch syndrome. All OCCPI study participants had their tumor samples analyzed using the traditional multi-test genetic testing approach and the single, upfront genomic tumor-sequencing test approach in which a single tumor sample was analyzed for multiple mutations simultaneously. Investigators compared results from the two screening methods and found that the upfront tumor-sequencing approach was more sensitive and more specific for detecting Lynch syndrome than the old, multiple-test model. Tumor sequencing resulted in a 10 percent improvement in Lynch syndrome detection rates while also providing important information about treatment options for the patients, according to study results. In addition, the study also identified eight patients (1.7%) with DYPD mutations. Patients with this mutation are prone to toxic reactions to 5-FU chemotherapy, which is commonly used to treat CRC. The researchers also found another eight patients had mutations in different hereditary cancer susceptibility genes which is important information for the patient and their family members. According to researchers, "offering this type of advanced genetic testing at the time of diagnosis could help guide and expedite treatment decisions for many patients who have CRC while simultaneously identifying the patients who are likely to have Lynch syndrome." While cost-analysis studies are necessary to determine if this is a cost-effective approach, the study authors concluded, "Up-front tumor sequencing in colorectal cancer is simpler and has superior sensitivity to current multitest approaches to Lynch syndrome screening, while simultaneously providing critical information for treatment selection."


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