Stratified mucin-producing intraepithelial lesion (SMILE) is an intraepithelial lesion with overlapping features of the high-grade squamous intraepithelial lesion (HSIL) and adenocarcinoma in situ (AIS). Currently, it is well described in the cervix. We present a case showing similar SMILE-like lesions in the polypectomy specimen from the anal canal along with invasive adenocarcinoma components. This lesion showed an immuno-profile characteristic of a SMILE lesion described in the cervix, such as p63 negativity, high ki67 index, and nuclear positivity for p16. It might be arising from the Human papillomavirus prone transitional region of the anal canal as described in the cervix. However, we could not assure this association and etiological link due to insufficient material in the formalin-fixed paraffin-embedded block. Notwithstanding, we strongly suggest that the HPV is the main driver for this SMILE-like lesion similar to what is described in the cervix. To our knowledge, this is the first case report of a SMILE lesion in the anal canal. Further studies will be required to elucidate the underlying pathogenetic mechanism of SMILE-like lesions described in the anal canal.

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Background: There is extensive crosstalk between the cyclin D–CDK4/6–inhibitor of CDK4–retinoblastoma and phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathways at the G1/S cell-cycle checkpoint. Both pathways are frequently dysregulated in hormone receptor-positive (HR+) breast cancer and have been associated with endocrine therapy (ET) resistance. CDK4/6 and PI3K/mTOR inhibitors have demonstrated clinical activity in combination with ET. Although CDK4/6 inhibitors combined with ET significantly improve progression-free survival (PFS) in ABC, disease progression eventually occurs, highlighting the need for effective treatment options following doublet therapy. Ribociclib (LEE011; CDK4/6 inhibitor; 3-weeks-on/1-week-off) + EVE (mTOR inhibitor) + EXE triplet therapy has shown preliminary clinical activity in heavily pretreated HR+, human epidermal growth factor receptor 2-negative (HER2–) ABC including patients (pts) with prior exposure to CDK4/6 inhibitors, suggesting this combination may restore sensitivity to CDK4/6 inhibitor-based therapy. Trial design and objectives: TRINITI-1 (NCT02732119) is a US-based, phase I/II, single arm, open-label study of ribociclib (continuous daily dosing) + EVE (2.5 mg/day) + EXE (25 mg/day) in men and postmenopausal women with HR+, HER2– ABC refractory to ≥1 line of ET. Phase I dose escalation consists of 2 ribociclib dose-level cohorts (250 and 300 mg/day), followed by a Simon Two-Stage phase II trial in pts with disease progression on prior CDK4/6 inhibitor-based therapy. No more than 3 lines of therapy for ABC, including ≤1 prior chemotherapy regimen, are permitted. Previous EXE treatment of >28 days for metastatic disease, prior mTOR inhibitors, and progression on >1 CDK4/6 inhibitor are prohibited. All pts in phase II must have progressed on a CDK4/6 inhibitor as the last regimen before study entry. Additional eligibility criteria include measurable disease or lytic/mixed bone lesions and Eastern Cooperative Oncology Group performance status of ≤1. Exclusion criteria include visceral crisis, unstable CNS metastases, and clinically significant heart disease. Phase I primary objective: maximum tolerated dose and/or recommended phase II dose of the triplet combination. Phase II primary objective: clinical benefit rate (CBR) at 24 weeks (0.1 significance level, 80% power to test CBR ≤15% against CBR ≥30%) with centrally-assessed PFS as a key secondary objective. Other secondary objectives include preliminary antitumor activity (phase I), safety and pharmacokinetics (phase I/II), and overall response rate, overall survival, and duration of overall response (phase II). Tumor assessments (RECIST v1.1) will be performed every 8 weeks for the first 12 months, and every 12 weeks thereafter until disease progression. Exploratory analyses include biomarkers potentially predictive of response and mechanisms of resistance. Target accrual: Approximately 52 pts at ∼30 sites; 3–6 pts per cohort in phase I, an initial 19 in phase II with another 20 enrolled upon demonstration of clinical benefit in ≥4 pts. Citation Format: Bardia A, Hurvitz S, Yardley DA, Zelnak A, DeMichele A, Clark AS, Warsi G, Small T, Tucci C, Moulder S. TRINITI-1: Ribociclib + everolimus (EVE) + exemestane (EXE) triplet combination in men or postmenopausal women with HR+, HER2– advanced breast cancer (ABC) following progression on a cyclin-dependent kinase (CDK) 4/6 inhibitor [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT2-01-05.

Background: Seviteronel (Sevi), a CYP17-lyase (L) inhibitor (reduces testosterone (T) and estradiol (E2) biosynthesis) and a competitive AR antagonist, has activity in castration resistant prostate cancer at a dose of 600mg nightly. Sevi potently inhibits the growth of ER(+)/AR(+) MCF7, tamoxifen-resistant (TAMR) MCF7, and ER(-)/AR(+) MDA-MB-453 cells. In a TAMR xenograft BC model, Sevi decreases tumor growth greater than enzalutamide (Enza), an AR antagonist (Ellison et al, SABCS 2015). Nearly all subtypes of BC, including AR(+) TNBC, are potential targets for Sevi based on its mechanism of action (MOA). Phase (Ph) 1 of this study established the recommended Ph 2 dose (RP2D) of Sevi in women with BC as 450mg once nightly, based upon preliminary tolerability and pharmacokinetics (PK) (Bardia et al, ASCO 2016). The primary objective of Ph 2 is to estimate the activity of Sevi, as measured by clinical benefit rate (CBR) at 16 and 24 weeks (wks) for AR(+) TNBC and ER(+) BC, respectively. The secondary objectives include an estimation of Sevi tolerability and pharmacodynamics (PD) (NCT02580448). Methods: Women with advanced AR(+) TNBC (stratified by prior Enza use) or ER(+) BC were enrolled using 3 parallel Simon's 2-stage designs powered to evaluate CBR. ER(+) BC patients must have had ≥1 prior line of endocrine therapy; no limit to prior treatment for TNBC. AR(+) status was confirmed using central IHC analysis in all patients, with a ≥10% tumor cell nuclear staining cutoff for evaluable TNBC patients. Sevi was administered once nightly with dinner at 450mg (28d cycle). Tumor and blood samples were collected for PK and PD analysis (circulating tumor cells, ctDNA, sex steroids). Response was assessed every 8 wks for 52 wks, then every 12 wks thereafter. Current tolerability and PD results are presented herein for this ongoing Ph 2 study. Results: As of June 7, 2016, 17 patients received Sevi at 450mg nightly between Ph1 and Ph2 with 10 in screening. 14 patients are currently on study in Cycles 1-6. The most common adverse events (AEs > 10% regardless of causality or grade) were tremor (24%), pain (18%), fatigue (18%) and dyspnea (18%), nausea (12%), AST increase (12%), ALT increase (12%) and abdominal pain (12%), all of which were Grade 1 or 2 except for Grade 3 dyspnea (n=1; unrelated). No dose reductions were reported and there were no drug-related discontinuations. Nine patients underwent central AR testing (4 AR(+) of 6 TNBC; 3 AR(+) of 3 ER(+) BC). Median AR tumor cell nuclear staining was 90% (15-100%). Preliminary sex steroid analyses from 6 Ph 1 patients receiving Sevi at 450, 600, or 750mg nightly (n=2 at each dose) for 1 cycle showed a median decline in E2 concentration of 52% (-29 to -87%) to 12.4pmol/L (4 to 33pmol/L) from baseline. There was a similar magnitude of decline for T. Conclusions: Sevi was well-tolerated at 450mg nightly with exposures similar to the RP2D in men (600mg nightly). The CYP17-L inhibition activity of Sevi was demonstrated with an early and potent reduction in E2 and T. Sevi's unique CYP17-L and AR antagonist MOA may provide a new novel treatment option for AR(+) TNBC or ER(+) BC. Citation Format: Gucalp A, Bardia A, Gabrail N, DaCosta N, Danso M, Elias AD, Ali H, Lemon SJ, Riley EC, Eisner JR, Fleming RA, Kurman MR, Moore WR, Traina TA. Phase 1/2 study of oral seviteronel (VT-464), a dual CYP17-lyase inhibitor and androgen receptor (AR) antagonist, in patients with advanced AR positive triple negative (TNBC) or estrogen receptor (ER) positive breast cancer (BC) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-08-04.

Identification and establishment of a correct clinical diagnosis of a distant metastasis from a follicular thyroid carcinoma is a challenging task. We believe that with prior knowledge of characteristic cytologic features, such metastases can be rapidly and accurately diagnosed by fine needle aspiration cytology.