Screening for colorectal cancer in asymptomatic average-risk adults: a guidance statement from the American College of Physicians (version 2)

The purpose of this updated guidance statement is to guide clinicians on screening for colorectal cancer (CRC) in asymptomatic average-risk adults. The intended audience is all clinicians. The population is asymptomatic adults at average risk for CRC. This updated guidance statement was developed using recently published and critically appraised clinical guidelines from national guideline developers since the publication of the American College of Physicians' 2019 guidance statement, "Screening for Colorectal Cancer in Asymptomatic Average-Risk Adults." The authors searched for national guidelines from the United States and other countries published in English using PubMed and the Guidelines International Network library from 1 January 2018 to 24 April 2023. The authors also searched for updates of guidelines included in the first version of our guidance statement. The Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument was used to assess the quality of eligible guidelines. Two guidelines were selected for adoption and adaptation by raters on the basis of the highest average overall AGREE II quality scores. The evidence reviews and modeling studies for these 2 guidelines were also used to synthesize the evidence of diagnostic test accuracy, effectiveness, and harms of CRC screening interventions and to develop our guidance statements.

Pre-surgical trial of the AKT inhibitor MK-2206 in patients with operable invasive breast cancer: a New York Cancer Consortium trial

Introduction: The PI3K/AKT/mTOR pathway is an oncogenic driver in breast cancer (BC). In this multi-center, pre-surgical study, we evaluated the tissue effects of the AKT inhibitor MK-2206 in women with stage I-III BC. Materials and methods: Two doses of weekly oral MK2206 were administered at days − 9 and − 2 before surgery. The primary endpoint was reduction of pAktSer473 in breast tumor tissue from diagnostic biopsy to surgery. Secondary endpoints included changes in PI3K/AKT pathway tumor markers, tumor proliferation (ki-67), insulin growth factor pathway blood markers, pharmacokinetics (PK), genomics, and MK-2206 tolerability. Paired t tests were used to compare biomarker changes in pre- and post-MK-2206, and two-sample t tests to compare with prospectively accrued untreated controls. Results: Despite dose reductions, the trial was discontinued after 12 patients due to grade III rash, mucositis, and pruritus. While there was a trend to reduction in pAKT after MK-2206 (p = 0.06), there was no significant change compared to controls (n = 5, p = 0.65). After MK-2206, no significant changes in ki-67, pS6, PTEN, or stathmin were observed. There was no significant association between dose level and PK (p = 0.11). Compared to controls, MK-2206 significantly increased serum glucose (p = 0.02), insulin (p < 0.01), C-peptide (p < 0.01), and a trend in IGFBP-3 (p = 0.06). Conclusion: While a trend to pAKT reduction after MK-2206 was observed, there was no significant change compared to controls. However, the accrued population was limited, due to toxicity being greater than expected. Pre-surgical trials can identify in vivo activity in the early drug development, but side effects must be considered in this healthy population

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