PracticeUpdate Oncology May 2019

ACRO 2019 23

Link Between GermlineMutations and Severe Radiation Toxicity Identified Findings highlight the need for additional research into genetic susceptibility to radiation and chemotherapy toxicity. S everal mutations leading to severe radiation toxicity have been dis- covered in a patient with prior grade 3 breast cancer. “Germline variants are mutations that are inherited and can increase the susceptibility to radiation toxicity,” Tyler J. Wilhite, MD, of the Mayo Clinic in Rochester told Elsevier’s PracticeUpdate . In this case study, a 46-year-old woman diagnosed in 1991 with grade 3 estrogen- and progesterone-receptor-positive ductal carcinoma of the breast approached the clinic with symptoms of late toxicity from radiation treatment given 25 years previously. At the time, she was treated with lumpectomy with left axillary nodal dissection as well as radiotherapy in the form of 50.4 Gy in 28 fractions to the left breast and regional lymph nodes, followed by 14.4 Gy boost to the lumpectomy bed at an outside hospital. She also received chemotherapy in the form of 6 cycles of cyclo- phosphamide, doxorubicin, and 5-FU. No sensitivities to radiotherapy were known prior to treatment. The patient presented to the investigators with painful chest wall fibrosis/ calcinosis requiring opiates. Earlier, she had experienced chest pain and pericardial infusion (2 years post-radiation treatment), sick sinus syndrome requiring a pacemaker as well as extensive soft tissue and cardiac calci- nosis (16 years post-radiation treatment), and pericardial thickening and tethering of the right ventricle to the liver capsule (21 years post-radiation treatment). Two years of treatment with hyperbaric oxygen, vitamin E, and pentoxifylline were not effective. The investigators conducted whole exome sequencing of her DNA to detect variants with the most deleterious 1% of possibilities within the human genome. Combined Annotation Dependent Depletion (CADD)-generated C-scores were used to determine relative pathogenicity of the variants. Typically, a scaled CADD C-score of 20 or more means that a variant is amongst the top 1% of deleterious variants in the human genome. Out of 5209 germline variants, they found mutations in three genes related to DNA replication and seven genes related to DNA repair. Four mutations in repair/replication genes had C-scores >20: MCM3 (C-score 27.2), DNA cross-link repair 1A protein (C-score 25.5), FANCI pro- tein (C-score 22.9), and Nibrin (C-score 24.2). Although these mutations have not been determined definitively to be correlated with radiation toxic- ity, they are associated with a plausible mechanism for potentially increased radiation-related toxicity, Dr. Wilhite explained. This study adds to evidence concerning the effect of germline mutations on radiation toxicity. For example, a germline ataxia telangiectasia-mutated gene was found to be associated with severe late toxicity in a woman with stage 2 invasive ductal carcinoma of the breast who had received adju- vant radiotherapy several years earlier. Similarly, a germline PTEN mutation was discovered to be associated with severe radiation toxicity in a patient with thyroid cancer. With the recent discoveries of genetic links to radiation and chemotherapy toxicity, some researchers are calling for more genome-wide studies that examine common and rare variants across the entire genome. It is hoped that this will eventually lead to a personalized approach to cancer treatment and allow the treatment team to choose an effective therapy that carries the least risk for toxicity. www.practiceupdate.com/c/81028

Mutant p53-expressing HNCC cells were found to be exquisitely sensitive to APR-246, compared with null and wild type HNCC cells, at low micromolar concen- trations. Overall, 35.8% growth inhibition was observed with p53 mutant R248L (FaDu) cells and 12.3% growth inhibition with R175H (Detroit) cells upon exposure to APR-246. No growth inhibition was seen with wild type or null cells. Additive effects were also seen when cells were first exposed to APR-246 and then treated with radiation. In p53 mutant FaDu cells, they found a 24.8% reduction in proliferation by a combination of APR-246 with radiation (4 Gy, P < .0001). In p53 mutant Detroit cells, they found a 24.4% reduction in proliferation by a combination of APR-246 with radiation (4 Gy, P < .0001). These results demonstrate that APR-246 displays differ- ential antiproliferative effects on human HPV-negative HNCC lines correlating with mutant p53 status. Effects are additive when combined with radiation. Dr. Nikolaev said that the next step for his lab is to test APR-486 in animal models of cancer. Studies are cur-

rently in the planning stage. www.practiceupdate.com/c/81052

VOL. 3 • NO. 2 • 2019