Burtness, Barbara

6016 Background: A germline mutation in let-7 complementary site 6 (LCS6) within the KRAS 3'-untranslated region (rs61764370, the KRAS-variant: TG/GG) is known to associate with poor outcome and drug resistance in various cancers compared to the wild type allele (TT). We examine the prognostic significance of the KRAS-variant in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). Methods: The KRAS-variant was determined in 116 tumor DNA samples from HNSCC patients enrolled in 3 clinical trials and a tissue collection study using a previously validated PCR-based assay. Results: KRAS-variant status could be determined in 108/116 (93%) samples and an allele frequency of TG/GG was 28.7%. These results were correlated with patient demographics, p16/human papillomavirus (HPV) status and clinical outcome. There was no association between p16/HPV status and the KRAS-variant status (Fisher’s exact test, p=1.0). The KRAS-variant was associated with poor progression-free survival in patients treated with cisplatin+/-cetuximab (log-rank p=0.002) but this association was not observed in docetaxel/bortezomib treated patients (log-rank p=0.89). Conclusions: KRAS-variant is a potentially promising biomarker of poor prognosis and a predictive biomarker of cisplatin resistance in R/M HNSCC. Prospective validation is warranted. Clinical trial information: NCT00003809.

6028 Background: Abnormalities in EGFR signaling targets are associated with C resistance but no biomarker of C resistance has been identified in HNSCC. We hypothesized that cases with loss of PTEN protein expression (PTEN null) or PIK3CA mutation would display C resistance in HNSCC. Methods: E5397 was a phase III trial of CDDP plus P or CDDP plus C and enrolled 117 eligible and evaluable pts. PIK3CA and PTEN were analyzed for 52 and 67 consented pts, respectively. PTEN expression (PTEN Cell Signaling Technology, Cat. 9559) was determined by automated quantitative analysis (AQUA) on the PM-2000 (HistoRx, New Haven) using a cutpoint generated in 5 HNSCC tissue microarrays, each consisting of HNSCC as well as positive (small intestine, median AQUA score 2833.2) and negative controls (breast and colon carcinoma, median AQUA score 205.5). A cutpoint of 570 provides 100% specificity, 100% sensitivity, and identified 30% of the HNSCCs as PTEN null, consonant with the literature. The 3 most common PIK3CA mutations (E542K and E545K in exon 9 and H1047R in exon 20) were determined by BEAMing (Inostics, Heidelberg, Germany). Response, overall survival (OS) and progression-free survival (PFS) were compared between PTEN null or PIK3CA mutated pts and all others. Log rank and multivariable Cox proportional hazards modeling were used to calculate p values. Results: 23/67 (34%) tumors were PTEN null and 2/52 (4%) had PIK3CA mutations (E542K and E545K). Both tumors with PIK3CA mutation had PTEN expression. No statistically significant differences in response, OS or PFS were noted in this small sample. However, among PTEN expressing/PIK3CA WT pts, median PFS increased to 4.2 months (m) for C (N=22) from 2.9 m for P (N=26) (Wald p=0.07), compared with 4.6 m for C (N=12) and 3.5 m for P (n=13) among the PTEN null/PIK3CA mutated (Wald p=0.60). Conclusions: The PTEN loss or PIK3CA mutation signature warrants further investigation as a predictor of C resistance.

6020 Background: A subset of salivary gland cancer (SGCs) express the androgen receptor (AR). This phase II trial evaluated the anti-androgen enzalumatide (Astellas) for patients with AR+ SGCs. Methods: Locally advanced/unresectable or metastatic AR+ SGCs were enrolled (AR status was centrally confirmed). Prior therapy with AR-targeted drugs was allowed. Enzalutamide 160 mg orally once daily was given (1 cycle= 28 days). The primary endpoint was confirmed response (RR) according to RECIST v1.1 within the first 8 cycles. Secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. A Simon-Optimal two-stage design was used to detect a 20% RR (vs. 5%) (alpha = 5%; beta = 90%). > 1 response(s) in the first 21 would trigger accrual to 41; > 4 responses would be considered promising. Results: 46 eligible patients (pts) were enrolled (40 M, 6 F; median age 65) in 22 months. In the first 21 pts, we initially had 2 confirmed PRs allowing for full study accrual, though one was later changed to stable disease. Among the 46 pts, 7 had PR as best response, though only 2 were confirmed within the first 8 cycles (4% (95% CI: 0.5-15%). Two other PRs did not count towards the primary endpoint due to 1) development beyond 8 cycles (cycles 12-18) and 2) a confirmatory scan completed <4 weeks apart. The other 3 pts with unconfirmed PR developed progression of disease (PD) after the first PR scan. 24 pts had stable disease; 15 pts PD as best response. Among 11 pts previously treated with AR-targeted therapy, best responses were 1 confirmed PR, 7 SD, 3 PD. With a median follow-up of 11.7 months (mo), OS at 12 mo was 66% (95% CI: 52-83%), PFS at 12 mo was 24% (95% CI: 14-42%), and median PFS was 5.5 mo (95% CI: 3.7-7.3). Conclusions: This is the first prospective trial evaluating an antiandrogen alone for AR+ SGCs. The failure to meet the protocol-defined measure of success was due in part to the lack of durability of initial responses. The clinical activity observed suggests the AR-dependence of AR+ SGCs, even among those previously treated with other hormonal therapies. Support: U10CA180821, U10CA180882; Astellas; https://acknowledgments.alliancefound.org. Clinical trial information: NCT02749903.

BACKGROUND13‐Cis retinoic acid (13‐CRA) is a synthetic vitamin A derivative. High‐dose 13‐CRA in patients with squamous cell cancers of the head and neck (SCCHNs) reduces the incidence of second primary tumors (SPTs). The authors report long‐term results from a phase 3 randomized trial that compared treatment with low‐dose 13‐CRA versus placebo for patients who had early stage SCCHN, with a focus on the development of SPTs and overall survival (OS).METHODSIn total, 176 patients who received treatment for stage I/II SCCHN were randomized to receive either low‐dose 13‐CRA (weight‐based dose of 7.5 mg or 10 mg) or placebo for 2 years. A competing‐risk approach and the log‐rank test were used to compare the time to SPT and OS, respectively, between groups.RESULTS13‐CRA neither significantly reduced the cumulative incidence of SPT (P = .61) nor improved the time to SPT (hazard ratio [HR] for 13‐CRA/placebo; 0.86; P = .61). Despite limited power, there was a trend toward improved OS for the 13‐CRA arm (HR, 0.75; P = .14), particularly among patients whose index tumor was surgically excised (N = 26; HR, 0.50; P = .057) and among women (N = 39; HR, 0.44; P = .065) and never/former smokers (N = 129; HR, 0.61; P = .055), with a median follow‐up of 16 years. The main 13‐CRA related toxicities were dry skin and cheilitis.CONCLUSIONSTreatment with low‐dose 13‐CRA for 2 years did not decrease the incidence of SPT; subset analysis indicates a potential survival advantage among patients who are women and never/former smokers. More targeted interventions based on clinical risk factors and molecular characterization of tumors may yield greater success in future prevention trials. Cancer 2017;123:4653‐4662. © 2017 American Cancer Society.