Citations

Abstract Endocrine therapy is underutilized to reduce breast cancer incidence among women at increased risk. Polygenic risk scores (PRSs) assessing 77 breast cancer genetic susceptibility loci personalizes risk estimates. We examined effect of personalized PRS breast cancer risk prediction on intention to take and endocrine therapy uptake among women at increased risk. Eligible participants had a 10-year breast cancer risk ≥5% by Tyrer–Cuzick model [International Breast Cancer Intervention Study (IBIS)] or ≥3.0 % 5-year Gail Model risk with no breast cancer history or hereditary breast cancer syndrome. Breast cancer risk was estimated, endocrine therapy options were discussed, and endocrine therapy intent was assessed at baseline. After genotyping, PRS-updated breast cancer risk estimates, endocrine therapy options, and intent to take endocrine therapy were reassessed; endocrine therapy uptake was assessed during follow-up. From March 2016 to October 2017, 151 patients were enrolled [median (range) age, 56.1 (36.0–76.4 years)]. Median 10-year and lifetime IBIS risks were 7.9% and 25.3%. Inclusion of PRS increased lifetime IBIS breast cancer risk estimates for 81 patients (53.6%) and reduced risk for 70 (46.4%). Of participants with increased breast cancer risk by PRS, 39 (41.9%) had greater intent to take endocrine therapy; of those with decreased breast cancer risk by PRS, 28 (46.7%) had less intent to take endocrine therapy (P < 0.001). On multivariable regression, increased breast cancer risk by PRS was associated with greater intent to take endocrine therapy (P < 0.001). Endocrine therapy uptake was greater among participants with increased breast cancer risk by PRS (53.4%) than with decreased risk (20.9%; P < 0.001). PRS testing influenced intent to take and endocrine therapy uptake. Assessing PRS effect on endocrine therapy adherence is needed. Prevention Relevance: Counseling women at increased breast cancer risk using polygenic risk score (PRS) risk estimates can significantly impact preventive endocrine therapy uptake. Further development of PRS testing to personalize breast cancer risk assessments and endocrine therapy counselling may serve to potentially reduce the incidence of breast cancer in the future.

The NCCN Guidelines for Colorectal Cancer (CRC) Screening describe various colorectal screening modalities as well as recommended screening schedules for patients at average or increased risk of developing sporadic CRC. They are intended to aid physicians with clinical decision-making regarding CRC screening for patients without defined genetic syndromes. These NCCN Guidelines Insights focus on select recent updates to the NCCN Guidelines, including a section on primary and secondary CRC prevention, and provide context for the panel’s recommendations regarding the age to initiate screening in average risk individuals and follow-up for low-risk adenomas.

This article is the work product of the Continuous Glucose Monitor and Automated Insulin Dosing Systems in the Hospital Consensus Guideline Panel, which was organized by Diabetes Technology Society and met virtually on April 23, 2020. The guideline panel consisted of 24 international experts in the use of continuous glucose monitors (CGMs) and automated insulin dosing (AID) systems representing adult endocrinology, pediatric endocrinology, obstetrics and gynecology, advanced practice nursing, diabetes care and education, clinical chemistry, bioengineering, and product liability law. The panelists reviewed the medical literature pertaining to five topics: (1) continuation of home CGMs after hospitalization, (2) initiation of CGMs in the hospital, (3) continuation of AID systems in the hospital, (4) logistics and hands-on care of hospitalized patients using CGMs and AID systems, and (5) data management of CGMs and AID systems in the hospital. The panelists then developed three types of recommendations for each topic, including clinical practice (to use the technology optimally), research (to improve the safety and effectiveness of the technology), and hospital policies (to build an environment for facilitating use of these devices) for each of the five topics. The panelists voted on 78 proposed recommendations. Based on the panel vote, 77 recommendations were classified as either strong or mild. One recommendation failed to reach consensus. Additional research is needed on CGMs and AID systems in the hospital setting regarding device accuracy, practices for deployment, data management, and achievable outcomes. This guideline is intended to support these technologies for the management of hospitalized patients with diabetes.

Case Report. Spine surgery in patients with Parkinson’s disease (PD) involves increased risk. We describe a case of cervical myelopathy in a patient with PD, multiple fractures involving the atlas and axis vertebrae, and spasmodic torticollis. The patient was successfully treated with an upper cervical decompression and occipital-cervical (OC) fusion surgery. Strategies for torticollis reduction and successful surgical outcome are discussed. Risks and benefits must be carefully weighed when considering occipital cervical fusion in PD patients. Conclusion. Intraoperative manual reduction of laterocollis is possible after general endotracheal anesthesia, and continuous neuromonitoring is established. Use of optimizing strategies such as perioperative botulinum injections and intraoperative O-arm navigation should be considered.

The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for diagnostic workup, staging, and treatment of patients with renal cell carcinoma (RCC). These NCCN Guidelines Insights focus on recent updates to the guidelines, including changes to certain systemic therapy recommendations for patients with relapsed or stage IV RCC. They also discuss the addition of a new section to the guidelines that identifies and describes the most common hereditary RCC syndromes and provides recommendations for genetic testing, surveillance, and/or treatment options for patients who are suspected or confirmed to have one of these syndromes.

Abstract New approaches are needed to overcome intrinsic therapy resistance in glioblastoma (GBM). Because GBMs exhibit sexual dimorphism and are reported to express steroid hormone receptors, we reasoned that signaling through the androgen receptor (AR) could mediate therapy resistance in GBM, as it does in AR-positive prostate and breast cancers. Using RNAseq, immunoblot and immunohistochemistry, we found that nearly half of GBM cell lines, patient-derived xenografts and human tumors express AR transcript and protein with levels that overlap those of primary prostate cancer. AR expression in GBM did not vary by sex, age or common molecular alterations. We identified two cell line models of GBM that expressed AR protein (LN18 and T98G: termed “AR positive”) and two that did not (8MGBA and AM38: termed “AR negative”). Seviteronel, a blood-brain barrier permeable CYP17 lyase inhibitor and antiandrogen slowed growth in AR positive GBM cell lines (GI50 3-4 µM) but not AR negative lines (GI50 > 500 µM) as measured by the colony formation assay. The antiandrogen enzalutamide, which also penetrates the blood brain barrier, similarly preferentially slowed growth in AR positive GBM cell lines. Seviteronel and enzalutamide sensitized AR positive GBM cell lines to radiation with enhancement ratios of 1.3-1.6 as measured by the clonogenic survival assay. Antiandrogens had no effect on the radiosensitivity of AR negative GBM cell lines. Seviteronel treatment did not affect the growth of AR positive T98G xenografts grown in vivo, but did sensitize these tumors to radiation (median time to tripling: 15 d with radiation alone and not reached with radiation combined with seviteronel). Enzalutamide similarly had modest single agent effects on an AR positive GBM patient-derived xenograft (GBM26 from the Mayo Clinic GBM PDX national resource) grown in vivo but sensitized these tumors to radiation (median time to tripling: 25.5 d with radiation alone and 39 d with radiation combined with enzalutamide). RNAseq performed on GBM26 tumors grown in vivo revealed that enzalutamide treatment caused minimal transcriptional changes when given as monotherapy but, when given in combination with radiation, blocked the ability of AR-positive GBMs to engage adaptive transcriptional programs related to multiple DNA repair pathways. We confirmed these mechanistic findings in vitro, as antiandrogens selectively impaired the repair of radiation-induced double strand DNA breaks in AR positive GBM cell lines. These results suggest that AR signaling may mediate therapy resistance in AR positive GBMs, and patients with these tumors could derive clinical benefit from combination therapies involving radiation and blood-brain-barrier permeable antiandrogens. Citation Format: Christian K. Werner, Uchechi Nna, Hanshi Sun, Kari Wilder-Romans, Joseph Dresser, Ayesha Kothari, Weihua Zhou, Yangyang Yao, Arvind Rao, Stefanie Stallard, Carl Koschmann, Tarik Bor, Waldemar Debinski, Alexander Hegedus, Meredith Morgan, Sriram Venneti, Edwina Baskin-Bey, Daniel Spratt, Howard Colman, Jann Sarkaria, Arul Chinnayain, Joel Eisner, Corey Speers, Theodore S. Lawrence, Roy Strowd, Daniel R. Wahl. Repurposing antiandrogens to overcome therapy resistance in androgen receptor-positive glioblastoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6267.