ESTRO 2021 Abstract Book

S89

ESTRO 2021

The cytosolic nucleic acid sensing cGAS-STING pathway has been identified as the key driver of radiotherapy induced immunogenic type-I interferon signalling. A critical initiating event for interferon production in response to radiotherapy has been identified as micronuclei generation. Nuclear membrane defects lead to rupturing of micronuclei and exposure of dsDNA in the cytosol to cGAS surveillance. Inhibition of the DNA damage response, as a monotherapy exploiting synthetic lethality, or in combination with radiotherapy, has been viewed as a promising therapeutic approach based on increased direct tumour cell cytotoxicity. These therapeutic modalities are now known to enhance micronuclei generation in combination with radiotherapy, potentiating radiation induced interferon signalling. Upon binding cytosolic dsDNA, cGAS produces the second messenger cGAMP, which subsequently binds and activates STING. cGAMP has been referred to as an ‘immunotransmitter’ due to its ability to diffuse to adjacent cells in the microenvironment, consequently activating STING in trans . Despite preclinical data showing tumour cGAS as a major driver for the remodelling of the inflammatory microenvironment, tumour cells are frequently defective in the type-I interferon signalling pathway. This indicates a reliance on non-tumour cell STING to drive cGAMP induced anti-tumour immune responses to radiotherapy. As such, anti-tumour immune responses to radiotherapy alone or in combination with DNA damage response inhibitors are likely to be determined by a mixture of factors. Tumour biology, tumour neoantigen profile, and the non-tumour cell populations of the tumour microenvironment. SP-0134 Should the majority of radiation treatments after breast conserving surgery consist if maximum 5 fractions? For the motion. C. Coles 1 1 University of Cambridge, Department of Oncology, Cambridge, United Kingdom Abstract Text Breast radiation therapy (RT) has been delivered traditionally as 25 daily 2 Gy fractions over 5 weeks. In the last 30 years, research investigating moderate hypofractionation with daily fractions of 2.5-3 Gy has demonstrated comparable 5-year rates of local recurrence and similar or better normal tissue effects with 3- week RT 1-4 . However, this high-quality research has been slow to be adopted internationally and 5-week RT is still practised in some RT centres worldwide. The UK FAST-Forward trial 5 was conducted in 97 UK hospitals in patients with early invasive breast carcinoma (pT1-3, pN0-1, M0) following surgery, and investigated 5-fraction-hypofractionation for whole breast RT delivered over one week. Participants were randomised to either 40 Gy in 15 fractions over 3 weeks, 27 Gy in 5 fractions over 1 week or 26 Gy in 5 fractions over 1 week; 4096 patients were recruited. At a median follow up of 71.5 months, 5-year cumulative incidence of the primary endpoint of local relapse was 2.1% (95% CI 1.4 to 3.1), 1.7% (1.2 to 2.6) and 1.4% (0.9 to 2.2) for the 40 Gy, 27 Gy and 26 Gy groups, respectively. The pre- specified non-inferiority criteria for both investigational groups excluded an increase in ipsilateral breast tumour relapse of 1.6% or more. Any moderate/marked clinician-assessed normal tissue effects at 5 years were 9.9%, 15.4% and 11.9% in the 40 Gy, 27 Gy and 26 Gy groups respectively. The odds ratios versus 40 Gy across all clinician assessments over follow-up were 1.55 (95% CI 1.32 to 1.83, p<0.0001) for 27 Gy and 1.12 (0.94 to 1.34, p=0.20) for 26 Gy. Both patient and photographic assessments showed a higher risk of normal tissue effects for 27 Gy, but not for 26 Gy, when compared with the control group. We will discuss why this high-quality trial supports the use of 5 fraction RT for the majority of patients after breast conserving surgery, within a whole spectrum of risk-adapted breast radiation treatments. Perceived concerns and barriers to practice change will be addressed in 3 key areas: · Ipsilateral breast tumour relapse · Normal tissue effects · Radiobiological considerations We will also highlight the need for all patients’ have access to 5 fraction RT where this is indicated and not to be denied their right to patient choice. Finally, we will discuss socio-economic advantages for patients, institutions and National Health Care Systems. References 1. Whelan T, MacKenzie R, Julian J, et al: Randomized trial of breast irradiation schedules after lumpectomy for women with lymph node-negative breast cancer. J Natl Cancer Inst 94:1143-50, 2002 2. Whelan TJ, Pignol JP, Levine MN, et al: Long-term results of hypofractionated radiation therapy for breast cancer. N Engl J Med 362:513-20, 2010 3. Group ST, Bentzen SM, Agrawal RK, et al: The UK Standardisation of Breast Radiotherapy (START) Trial A of radiotherapy hypofractionation for treatment of early breast cancer: a randomised trial. Lancet Oncol 9:331-41, 2008 4. Haviland JS, Owen JR, Dewar JA, et al: The UK Standardisation of Breast Radiotherapy (START) trials of radiotherapy hypofractionation for treatment of early breast cancer: 10-year follow-up results of two randomised controlled trials. Lancet Oncol 14:1086-1094, 2013 5. Murray Brunt A, Haviland JS, Wheatley DA, et al: Hypofractionated breast radiotherapy for 1 week versus 3 weeks (FAST-Forward): 5-year efficacy and late normal tissue effects results from a multicentre, non- inferiority, randomised, phase 3 trial. Lancet 395:1613-1626, 2020 Debate: Should the majority of radiation treatments after breast conserving surgery consist of maximum 5 fractions?

SP-0135 Against the motion B. Offersen Denmark