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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.



Distinct molecular profiles and immunotherapy treatment outcomes of V600E and V600K BRAF-mutant melanoma

Unlike patients with melanoma bearing BRAF V600E mutations, those whose tumors have V600K mutations may benefit less from BRAF and MEK inhibitors and more from anti-PD-1 immunotherapy, according to a recent study (Clin Can Res 2019; doi:10.1158/1078-0432.CCR-18-1680). Researchers evaluated baseline samples taken from 93 BRAF-mutant melanoma patients treated with targeted therapy (BRAF inhibitors with or without MEK inhibitors). Of those patients, 73 had V600E BRAF-mutant melanoma, while 15 patients had V600K BRAF-mutant melanoma. The investigators analyzed baseline samples with gene expression profiling and DNA sequencing, and mutant genotypes were correlated with clinical outcomes. An independent cohort of 103 BRAF-mutant melanoma patients that were treated with anti-PD-1 immunotherapy (pembrolizumab or nivolumab) were also evaluated. Of this cohort, 84 had V600E BRAF-mutant melanoma, while 19 patients had V600K BRAF-mutant melanoma. Response to immunotherapy based on BRAF genotype was correlated with clinical outcomes. Patients in the targeted therapy group with V600K mutations had less tumor regression and shorter progression-free survival compared to patient with V600E mutations. However, researchers noted that the differences were not statistically significant. Among patients in the immunotherapy cohort with V600K mutations, progression-free survival was significantly higher compared with patients with V600E mutations (median of 19 and 2.7 months, respectively). The findings showed that, among baseline tumor samples in the targeted therapy cohort, patients harboring V600K BRAF mutations had a significantly higher mutational load compared to those with V600E BRAF mutations. "BRAF V600K melanomas appear to benefit less from BRAFi+/-MEKi than V600E, potentially due to less reliance on ERK pathway activation and greater use of alternative pathways," study authors concluded. "In contrast, these melanomas have higher mutational load and respond better to immunotherapy."



Variations in HPV function are associated with survival in squamous cell carcinoma

Through the analysis of variations in the level of human papillomavirus (HPV) in head and neck cancers, researchers have discovered a gene signature associated with treatment response and survival in patients (JCI Insight 2019; doi:10.1172/jci.insight.124762). Data was analyzed from 80 oropharyngeal cancers included in The Cancer Genome Atlas. Going beyond classifying tumors as HPV-positive or HPV-negative, the researchers examined all tumors based on their level of HPV gene expression. An initial panel of 582 genes was found that distinguished these three subgroups-a high HPV group, a low HPV group, and an HPV-negative group-each with statistically significant survival differences. Further analyses led to a panel of just 38 genes that are able to distinguish between the two HPV-positive subgroups, according to the researchers. The team discovered two viral genes not generally thought to be important for tumor progression that were significantly different between the HPV-positive groups. Further, cell line studies showed these genes to be correlated with radiation sensitivity, in alignment with responses seen in patients. "We developed a prognostic biomarker signature for identification of this subgroup of HPV-positive oropharyngeal squamous cell carcinoma and validated it in independent cohorts of oropharyngeal and cervical carcinomas," the researchers wrote. "These findings could translate to improved patient stratification for treatment deintensification and new therapeutic approaches for treatment-resistant HPV-related cancer."



PROREPAIR-B: a prospective cohort study of the impact of germline DNA repair mutations on the outcomes of patients with metastatic castration-resistant prostate cancer

Aggressive prostate cancer is associated with BRCA2 mutations, which are also linked to hereditary breast cancer, ovarian cancer, and pancreas cancer, among others (J Clin Oncol 2019; doi:10.1200/JCO.18.00358). The findings revealed that family members of patients with prostate cancer who carry BRCA2 and DNA-repair gene mutations have an increased risk of developing cancer. Additionally, the study showed that prostate cancer in men with BRCA2 mutations is associated with worse outcomes and poor responses to standard treatments. More than 400 men diagnosed with prostate cancer resistant to castration were followed up for 5 years starting in 2013 in order to analyze their genetic characteristics and the impact of these on the progression of the disease and response to treatments. Researchers identified 68 carriers (16.2%) of 419 eligible patients, including 14 with BRCA2, eight with ATM, four with BRCA1, and none with PALB2 mutations. "Significant interactions between germline BRCA2 status and treatment type (androgen signaling inhibitor vs. taxane therapy) were observed," study authors reported. "Cause-specific survival (24.0 vs. 17.0 months) and progression on the second systemic therapy (18.9 vs. 8.6 months) were greater in germline BRCA2 carriers treated in first line with abiraterone or enzalutamide compared with taxanes." They concluded that "determination of germline BRCA2 status may be of assistance for the selection of the initial treatment in metastatic castration-resistance prostate cancer."



Breast cancer risk after recent childbirth: a pooled analysis of 15 prospective studies

Younger women who have recently had a child may have a higher risk of breast cancer than their peers of the same age who do not have children, according to a recent study (Ann Intern Med. 2019;170(1):22-30). Researchers pooled data from 15 prospective studies from the around the globe that included 889,944 women. They looked at breast cancer risk after childbirth; in addition, the researchers evaluated the impact of other factors, such as breastfeeding and a family history of breast cancer. The findings showed that among women 55 years and younger, breast cancer risk peaked about 5 years after they gave birth, with risk for mothers 80 percent higher compared with women who did not give birth. Twenty-three years after giving birth, women saw their risk level off, and pregnancy started to become protective, researchers reported. "Increases in breast cancer risk after childbirth were pronounced when combined with a family history of breast cancer and were greater for women who were older at first birth or who had more births. Breastfeeding did not modify overall risk patterns," according to study authors. Findings demonstrated that risk was higher for women who had their first child after 35, but there was no increased risk of breast cancer after a recent birth for women who had their first child before 25. "Compared with nulliparous women, parous women have an increased risk for breast cancer for more than 20 years after childbirth," the researchers concluded. "Health care providers should consider recent childbirth a risk factor for breast cancer in young women."


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