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Summary Background Whole breast irradiation delivered once per day over 3–5 weeks after breast conserving surgery reduces local recurrence with good cosmetic results. Accelerated partial breast irradiation (APBI) delivered over 1 week to the tumour bed was developed to provide a more convenient treatment. In this trial, we investigated if external beam APBI was non-inferior to whole breast irradiation. Methods We did this multicentre, randomised, non-inferiority trial in 33 cancer centres in Canada, Australia and New Zealand. Women aged 40 years or older with ductal carcinoma in situ or node-negative breast cancer treated by breast conserving surgery were randomly assigned (1:1) to receive either external beam APBI (38·5 Gy in ten fractions delivered twice per day over 5–8 days) or whole breast irradiation (42·5 Gy in 16 fractions once per day over 21 days, or 50 Gy in 25 fractions once per day over 35 days). Patients and clinicans were not masked to treatment assignment. The primary outcome was ipsilateral breast tumour recurrence (IBTR), analysed by intention to treat. The trial was designed on the basis of an expected 5 year IBTR rate of 1·5% in the whole breast irradiation group with 85% power to exclude a 1·5% increase in the APBI group; non-inferiority was shown if the upper limit of the two-sided 90% CI for the IBTR hazard ratio (HR) was less than 2·02. This trial is registered with ClinicalTrials.gov , NCT00282035 . Findings Between Feb 7, 2006, and July 15, 2011, we enrolled 2135 women. 1070 were randomly assigned to receive APBI and 1065 were assigned to receive whole breast irradiation. Six patients in the APBI group withdrew before treatment, four more did not receive radiotherapy, and 16 patients received whole breast irradiation. In the whole breast irradiation group, 16 patients withdrew, and two more did not receive radiotherapy. In the APBI group, a further 14 patients were lost to follow-up and nine patients withdrew during the follow-up period. In the whole breast irradiation group, 20 patients were lost to follow-up and 35 withdrew during follow-up. Median follow-up was 8·6 years (IQR 7·3–9·9). The 8-year cumulative rates of IBTR were 3·0% (95% CI 1·9–4·0) in the APBI group and 2·8% (1·8–3·9) in the whole breast irradiation group. The HR for APBI versus whole breast radiation was 1·27 (90% CI 0·84–1·91). Acute radiation toxicity (grade ≥2, within 3 months of radiotherapy start) occurred less frequently in patients treated with APBI (300 [28%] of 1070 patients) than whole breast irradiation (484 [45%] of 1065 patients, p Interpretation External beam APBI was non-inferior to whole breast irradiation in preventing IBTR. Although less acute toxicity was observed, the regimen used was associated with an increase in moderate late toxicity and adverse cosmesis, which might be related to the twice per day treatment. Other approaches, such as treatment once per day, might not adversely affect cosmesis and should be studied. Funding Canadian Institutes for Health Research and Canadian Breast Cancer Research Alliance.

The efficacy of immunotherapy targeting the PD-1/PD-L1 pathway has previously been demonstrated in metastatic head and neck squamous cell carcinoma (HNSCC). Stereotactic Body Radiotherapy (SBRT) aims at ablating metastatic lesions and may play a synergistic role with immunotherapy. The purpose of this study is to assess the safety and efficacy of triple treatment combination (TTC) consisting of the administration of durvalumab and tremelimumab in combination with SBRT in metastatic HNSCC. This is a phase I/II single arm study that will include 35 patients with 2–10 extracranial metastatic lesions. Patients will receive durvalumab (1500 mg IV every 4 weeks (Q4W)) and tremelimumab (75 mg IV Q4W for a total of 4 doses) until progression, unacceptable toxicity or patient withdrawal. SBRT to 2–5 metastases will be administered between cycles 2 and 3 of immunotherapy. The safety of the treatment combination will be evaluated through assessment of TTC-related toxicities, defined as grade 3–5 toxicities based on Common Terminology Criteria for Adverse Events (v 4.03), occurring within 6 weeks from SBRT start, and that are definitely, probably or possibly related to the combination of all treatments. We hypothesize that dual targeting of PD-L1 and CTLA-4 pathways combined with SBRT will lead to

Genetic factors behind the increasing incidence of human papillomavirus (HPV) negative head and neck squamous cell carcinoma (HNSCC) in young non-smokers are suspected, but have not been identified. Recently, rs6942067, a single nucleotide polymorphism (SNP) located upstream of the DCBLD1 gene, was found associated with non-smoking lung adenocarcinoma. To validate if this SNP is also implicated in HNSCC, participants of The Cancer Genome Atlas HNSCC cohort were investigated for rs6942067 status, associated DCBLD1 expression, and clinical characteristics. Occurrence of the rs6942067 GG genotype is significantly higher in young and in HPV negative non-smoking HNSCC than in other HNSCC. Additionally, rs6942067 GG is associated with higher DCBLD1 expression in HNSCC and patients with high DCBLD1 expression have a worse overall survival at three years, both in univariate and multivariate analysis. Furthermore, high DCBLD1 expression is associated with activation of the integrin signaling pathway and its phosphorylation with EGFR and MET. Collectively, these findings suggest that DCBLD1 plays a critical role in HNSCC and demonstrate an association between rs6942067 and clinical characteristics of young age and HPV negative non-smoking status in HNSCC patients.

Genomic analyses of head and neck squamous cell carcinoma (HNSCC) have highlighted alterations in the phosphatidylinositol 3-kinase (PI3K) signaling pathway, presenting a therapeutic target for multiple ongoing clinical trials with PI3K or PI3K/MTOR inhibitors. However, these inhibitors can potentially increase autophagy in HNSCC and indirectly support cancer cell survival. Here, we sought to understand the relationship between the PI3K signaling pathway and autophagy during their dual inhibition in a panel of HNSCC cell lines. We used acridine orange staining, immunoblotting, and tandem sensor Red Fluorescent Protein- Green Fluorescent Protein-, microtubule-associated protein 1 light chain 3 beta (RFP-GFP-LC3B) expression analysis to show that PI3K inhibitors increase autophagosomes in HNSCC cells, but that chloroquine treatment effectively inhibits the autophagy that is induced by PI3K inhibitors. Using the Bliss independence model, we determined that the combination of chloroquine with PI3K inhibitors works in synergy to decrease cancer cell proliferation, independent of the PIK3CA status of the cell line. Our results indicate that a strategy focusing on autophagy inhibition enhances the efficacy of therapeutics already in clinical trials. Our results suggest a broader application for this combination therapy that can be promptly translated to in vivo studies.

6531 Background: PD-1/PD-L1 +/- CTLA-4 blockade in head-and-neck carcinoma (HNSCC) has shown signs of clinical activity. SBRT aims to reduce tumor burden and perhaps be immune-stimulatory. This analysis seeks to assess the safety and efficacy signal of the triple treatment combination (TTC) consisting of SBRT sandwiched between cycles of D (αPD-L1) and T (αCTLA-4) in oligometastatic (2-10) HNSCC. Methods: This is a single arm multi-institutional phase I/II trial (NCT03283605). D (1500 mg) and T (75 mg) were given for 4 monthly cycles, followed by monthly D. SBRT to 2-5 lesions was administered during cycle 2. The median prescribed and maximum SBRT doses were 40 Gy (range:18-50) and 49 Gy (range:28-61), respectively, given in 3-5 fractions. Global health status was derived from EORTC QLQ C30 questionnaires. Results: At data cut-off (Dec 31, 2019), 20 patients were recruited, of which 16 had a study treatment and were analyzed. Table describes the patient characteristics. There were 1 CTCAE V5.0 Grade 2 and 1 Grade 3 (both GI) serious adverse event (SAE) attributable to D and T. Two patients had unrelated SAEs (1 Grade 3-hypercalcemia and 1 Grade 5-GI). The Grade 5 SAE was a gastric hemorrhage that occurred the night of the first D + T infusion. There was no Grade 3+ AE secondary to SBRT. Thus, SBRT did not add to the 2/16 patients who had D + T related SAEs. Global health status scores did not differ statistically between baseline (75) and cycle 3 (73). Of the 14 patients that received SBRT, 7 patients had RECIST target lesions untreated by SBRT. The best responses for these 7 patients were: 1 CR, 3 PR, and 3 SD. When SBRT treated lesions are included and analyzed per RECIST (n = 14), there were 9 PR, 3 SD and 2 PD. The estimated median progression free survival was 7.2 months. Conclusions: The first 16 evaluable patients demonstrated tolerable profiles to the TTC (D + T + SBRT) for the treatment of oligometastatic (≤10 lesions) HNSCC. Best response rates were encouraging and could be due to the addition of SBRT during immunotherapy that served to either stimulate the immune system or annihilate slow responding or immunotherapy resistant lesions. Smaller overall tumor burden and 7/16 patients being treated in first line could also have contributed to better results. Clinical trial information: NCT03283605 . [Table: see text]

6580 Background: The combination of carboplatin and 5-fluorouracil (5-FU) is effective when used concurrently with radiotherapy for locoregionally advanced oropharyngeal carcinomas (Calais et al. 1999). DPYD polymorphisms can be associated with an increased risk of severe toxicity to fluoropyrimidines (Deenen et al. 2016). Upfront screening for the DPYD*2A allele is available in the province of Québec, Canada since March 2017. This study aimed to determine the effect of upfront genotyping on grade ≥3 toxicities. Methods: The studied population included all consecutive cases of oropharyngeal carcinomas treated with 5-FU based chemoradiotherapy one year before and after the implementation of upfront DPYD*2A genotyping. All patients were treated at the Centre Hospitalier de l’Université de Montréal (CHUM) between March 2016 and April 2018. Clinical data were extracted from chart review. Extended screening for 3 supplemental at-risk DPYD variants was also retrospectively performed in August 2019. Results: 181 patients were included in the analysis (87 patients before and 94 patients after DPYD*2A screening implementation). 91% of patients (n = 86) were prospectively genotyped for the DPYD*2A allele. Of those screened, 2% (n = 2/87) demonstrated a heterozygous DPYD*2A mutation. Those two patients received cisplatin-based treatment and thus avoided 5-FU toxicities. Extended genotyping of DPYD*2A-negative patients later allowed for the retrospective identification of 6 additional patients with alternative DPYD variants (two c.2846A > T and four c.1236G > A allele mutations). Conclusions: The DPYD*2A, c.2846A > T and c.1236G > A polymorphisms are associated with an increased risk of G3-4 toxicity to 5-FU, as well as higher hospitalization rates. Upfront DPYD genotyping can identify patients in whom fluoropyrimidine-related toxicity should be avoided. This represents an interesting addition in terms of pharmacovigilance. [Table: see text]

Intensity-modulated radiotherapy (IMRT) is a modern treatment technique that allows one to shape the dose to the target volume and to reduce the dose delivered to healthy tissue. Over the last decade, IMRT has been implemented for head and neck cancer treatment, with the aim of reducing the dose delivered to the parotid glands and improving the dose coverage of complex target volumes located close to critical structures. The potential benefits of IMRT in terms of salivary function preservation and better local control have contributed to the rapid diffusion of this new technology. However, it should not be overlooked that IMRT is a novel treatment technique and that its clinical application represents a paradigm shift in the practice of radiation oncology. The purpose of this article is to review the clinical experience with IMRT for head and neck cancer treatment and to discuss some important issues related to its implementation.

Objective To determine the feasibility and toxicity profile of accelerated radiotherapy with a simultaneous integrated boost fractionation scheme with intensity-modulated radiotherapy (SIB-IMRT) with or without chemotherapy. Study Design and Setting Forty-nine patients with advanced head and neck cancer underwent SIB-IMRT. Concomitant chemotherapy was administered in 29 patients. Results Grade 3 acute toxicities included 55% mucositis, 20% odynophagia, 12% nausea, 18% hematologic, and 8% skin. There were no grade 4 toxicities or treatment-related deaths. With a median follow-up of 25 months, locoregional control was 83%, and overall survival was 80%. Of patients with grade 3 late toxicities, two patients (4% of the total) required a permanent percutaneous endoscopic gastrostomy tube, and osteonecrosis occurred in one patient (2% of the total). Conclusions SIB-IMRT is a feasible technique that shortens the overall treatment time in the radical treatment of patients with advanced head and neck cancer while maintaining acceptable rates of acute toxicity in this study. Although the results are promising, this approach should be considered only in the setting of a clinical trial.