Background:Adaptive radiotherapy is being used in few institutions in patients with head and neck cancer having bulky disease using periodic computed tomography imaging accounting for volumetric changes in tumor volume and/or weight loss. Limited data are available on ART in the postoperative setting. We aim to identify parameters that would predict the need for ART in patients with head and neck cancer and whether ART should be applied in postoperative setting.Materials and Methods:Twenty patients with stage III–IV head and neck cancer were prospectively accrued. A computed tomography simulation was done prior to treatment and repeated at weeks 3 and 6 of concurrent intensity-modulated radiotherapy and chemotherapy. The final plan was coregistered with the subsequent computed tomography images, and dosimetric/volumetric changes at weeks 1 (baseline), 3, and 6 were quantified in high-risk clinical target volumes, low-risk clinical target volumes , right parotid , left parotid , and spinal cord . An event to trigger ART was defined as spinal cord maximum dose >45 Gy, parotid mean dose >26 Gy, and clinical target volume coverage <95%.Results:Comparing the 2 groups, the proportion of patients with at least 1 event triggering ART was higher in bulky disease than in postoperative group: 72.7% versus 18.2% (P = .03) overall; 54.6% versus 1.8% (P = .064) at week 3; and 63.6% versus 18.2% (P = .081) at week 6. In the bulky disease group, 8 of 11 patients had events at week 3 and/or 6 as follows: overdose in spinal cord (n = 2), right parotid (n = 3), left parotid (n = 5), coverage < 95% seen in low-risk clinical target volumes (n = 3), and high-risk clinical target volumes (n = 5). In the postoperative group, 2 of 11 patients had events: spinal cord (n = 1) and low-risk clinical target volume (n = 1).Conclusion:Our study confirmed the need for ART in patients with head and neck cancer having bulky disease due to target under dosing and/or spinal cord/parotids overdosing in weeks 3 and 6. In contrast, the benefit of ART in postoperative patients is less clear.

e14048 Background: DNA-PK, with its protein subunits, Ku70 and Ku80, regulates one of the major pathways responsible for repair of double-strand breaks in DNA that are induced by radiotherapy (RT) and some chemotherapeutic agents (CT). Therefore, the combined strategy of RT with a DNA-PKi is promising. The purpose of this phase I trial is to explore the safety, tolerability, pharmacokinetic (PK) profile, and clinical activity of M3814 administered together with RT and chemo-RT (CRT). Methods: Patients (pts) with tumors or metastasis in the head and neck region or thorax in need of palliative RT (10 x 3 Gy) are eligible for the dose escalation part Ia, with a starting dose of 100 mg once daily. Dose escalation decisions are aided by the Bayesian logistic regression model with overdose control. Dose-limiting toxicity (DLT) is evaluated up to 3 weeks after RT. Rich PK sampling is taken during treatment. Tumor evaluation is performed every 6 weeks up to 6 months and every third month thereafter. Results: As of January 2017, 7 pts had been enrolled into the part Ia dose escalation arm and treated with 100 mg daily. The most frequent adverse events (AEs) were fatigue, constipation, decreased appetite, dry mouth, dysphagia, headache, oral pain, radiation skin injury, and mucositis in more than 1 pt (20%). No pts discontinued due to AE. Two episodes of grade 3 mucositis lasting > 7 days were reported; one of these was classified as a DLT, and both pts recovered without sequelae. Two of 7 pts enrolled had local tumor control at +300 days. PK analysis demonstrated high exposure variability. Conclusions: M3814 at the 100 mg daily dose was tolerable as palliative treatment and dose escalation is currently at 200 mg. In part Ib of the study, two separate dose escalation arms will enroll pts with either head and neck squamous cell carcinoma (SCCHN; US only) or non-small cell lung cancer (EU and US) to receive CRT 2 Gy x 30-35 over 6-7 weeks with curative intent; the SCCHN cohort is now open for enrollment. For these two cohorts, the DLT window will be 12 weeks. Clinical trial information: NCT02516813.

Background: We developed SET4 as a targeted, droplet-based, next-generation RNA sequencing assay to measure both the SETER/PR index of gene expression and the percent of estrogen receptor (ER) transcripts with point mutation in the ligand-binding domain (LBD) in metastatic biopsies of Stage IV breast cancer. The SETER/PR index (31 genes) is a cumulative measure of gene expression for transcripts associated with ER and progesterone receptor (PR), excluding those with a direct role in proliferation. High SETER/PR could indicate increased sensitivity to endocrine therapy, whereas LBD mutations indicate resistance but might also induce high SETER/PR. Methods: Targeted needle biopsies from a metastatic site were prospectively obtained from 82 patients with HR+/HER2- breast cancer at time of any progression event, and preserved in RNAlater. Samples were prepared for targeted sequencing on a MiSeq by combining purified total RNA with SET4 primers and RT-PCR master mix into single molecule-formatted picodroplets using a RainDrop Source instrument, followed by thermal cycling and sample indexing. Calculated SETER/PR index and percent ER transcripts with LBD mutations were evaluated as continuous variables and compared to progression-free and overall survival using Cox regression analysis with log-rank test, if the next treatment after biopsy included endocrine therapy. Results: The average read depth for the LBD of the ER transcript was 33,475X (range: 1230-180,889X), confidently detecting mutation at 1% frequency. LBD mutations were identified in 17% (14/82) of metastases (range of mutated transcripts 1%-98%). LBD mutations (&gt;10% of transcripts) were only observed in metastases with higher SETER/PR (above the median). In patients who next received endocrine therapy (n=58), higher SETER/PR predicted longer progression-free (PFS) (HR=0.37, p=0.0004, Δ median PFS 9 months) and overall survival (OS) (HR=0.49, p=0.03). The predictions were more pronounced in patients without LBD mutation (PFS HR=0.32, p=0.0001, Δ median PFS 13 months; OS HR=0.42, p=0.01). Currently, there are insufficient cases with LBD mutation for reliable survival analysis. Conclusion: The SET4 assay measured the percent of ER transcripts with activating LBD mutation (≥1% prevalence) and also downstream ER/PR-related transcription. High SETER/PR predicted longer PFS and OS with endocrine therapy. While activating LBD mutations may be associated with endocrine resistance of Stage IV cancer, they were associated with high SETER/PR index. Consequently, metastatic cancers with high SETER/PR index and no LBD mutation in ER transcripts were particularly sensitive to endocrine therapy. This single assay unraveled a possible interaction between genotype, phenotype, and treatment outcome; and is currently being evaluated in a larger cohort of patients. Citation Format: Rosanna Lau, Lily Fu, Michael Samuels, Rashmi K. Murthy, Bruno Sinn, Jane Yu, Rebekah Gould, Jennifer Litton, Alda Tam, Stacy Moulder, Daniel Booser, Debu Tripathy, Vicente Valero, Fraser Symmans. A targeted RNA-seq assay to measure activating ER mutations and ER/PR-associated gene expression predicts sensitivity to endocrine therapy for metastatic breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1796. doi:10.1158/1538-7445.AM2017-1796

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