Faculty Bibliography

INTRODUCTION/BACKGROUND: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/METHODS: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/CONCLUSIONS: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.

BACKGROUND:Anal squamous cell carcinoma (ASCC) incidence has been rising over the past decade, most dramatically in HIV-positive men who have sex with men (MSM). We aimed to identify a novel in-office approach for ablating high-grade anal intraepithelial neoplasia (HGAIN), the believed precursor lesion to ASCC. MATERIALS AND METHODS/METHODS:We performed a retrospective analysis of medical records from a New York City surgical practice, identifying patients with HGAIN treated with electrocautery ablation (ECA) and followed for at least 5 months with high-resolution anoscopy, biopsies, and/or cytology. We sought to determine HGAIN recurrence and progression to ASCC after ECA. RESULTS:Two hundred thirty-two MSM, 132 HIV positive and 100 HIV negative, with median follow-up of 19.0 and 17.5 months, respectively, met inclusion criterion. In HIV-negative and HIV-positive MSM, the probability of curing a lesion after first ECA was 85% and 75%, respectively. Over follow-up, 53% of HIV-negative and 61% of HIV-positive patients recurred. After first and second ECA, HIV-positive MSM were 1.28 times (P = 0.16) and 2.34 times (P = 0.009) more likely to recur than HIV-negative MSM. The majority of recurrence was due to development of additional lesions at untreated sites (metachronous recurrence). One patient (0.4%) developed ASCC. At last visit, 83% of HIV-negative and 69% of HIV-positive patients were HGAIN free. CONCLUSIONS:ECA is an effective treatment for HGAIN, with fewer patients progressing to ASCC than predicted with expectant management. HIV-positive patients are significantly more likely to recur than HIV-negative patients.