Educational Session 3: Refining Local Therapy in Multidisciplinary Care

B. V. Offersen¹, A. W. M. Nielsen², L. B. J. Thorsen², D. Özcan², L. W. Matthiessen³, E. Maae⁴, M. L. H. Milo⁵, M. H. Nielsen⁶, T. Tramm², J. Overgaard²; ¹Dept Experimental Clinical Oncology, Aarhus, DENMARK, ²Dept Experimental Clinical Oncology, Aarhus University Hospital, DENMARK, ³Department of Oncology, Copenhagen University Hospital Herlev and Gentofte, DENMARK, ⁴Dept Oncology, Vejle Hospital, University Hospital of Southern DK, DENMARK, ⁵Dept Oncology, Aalborg University Hospital, DENMARK, ⁶Dept Oncology, Odense University Hospital, DENMARK.

Background: Internal mammary node irradiation (IMNI) improves overall survival (OS) in node-positive breast cancer patients. However, the effect is not documented in breast cancer patients treated with newer systemic therapies and3D-based radiotherapy (RT). Therefore, the Danish Breast Cancer Group (DBCG) IMN2 study aimed to investigate the effect of IMNI in node-positive breast cancer patients treated with newer systemic therapies and 3D-based RT.Methods: DBCG IMN2 was a nationwide population-based cohort study prospectively allocating node-positive breast cancer patients with right-sided tumours to IMNI and patients with left-sided tumours to no IMNI in six RT centres. RT dose was 50Gy/25fr, and the recommended regional dose was 90-107%. Exclusion criteria were prior malignancies, bilateral breast cancer, neoadjuvant systemic therapy, recurrence before RT, or non-standard RT. Systemic treatment included taxane-based chemotherapy, aromatase inhibitors, and trastuzumab. The primary end-point was OS. Secondary endpoints were breast cancer mortality and distant metastasis. Cox regression analyses were used for adjusted hazard ratios (HR). Quality assurance (QA) of the RT included re-delineation of the IMN irrespective laterality using the ESTRO guidelines.Findings: In the period January 2007-May 2014, a total of 4541 patients were included. Patient and tumour characteristics were distributed evenly between right- and left-sided patients. RT plans for 2837 patients (62.5%) were available and showed comparable dose coverage between the clinically used IMN delineation and the re-delineated IMN_ESTRO. Comparing IMN_ESTRO_IC1-3 in all patients by laterality, the median CTVn_V90% was 94.6 % (IQR 64.8-100.0) in right-sided patients and 20.4% (IQR 0.9-55.8) in left-sided patients, p < 0.001. Median mean heart doses were lower in right-sided patients (1.2 Gy) than in left-sided (2.3 Gy), p < 0.001. Median mean lung doses were higher in right-sided patients (16.0 Gy) than in left-sided (12.7 Gy), p < 0.001. Median follow-up was 13.7 years for OS. Survival rates at 15 years were 65.0% in patients with IMNI and 60.8% without IMNI leading to an adjusted HR of 0.85 (95% CI, 0.76-0.94; p = 0.0016) for OS. Corresponding HRs were 0.84 (95% CI, 0.74-0.95; p = 0.0077) for breast cancer mortality and HR 0.87 (95% CI, 0.78-0.98; p = 0.026) for distant metastasis. No subgroups were identified for the omission of IMNI. In the 3100 patients with pN1 disease, IMNI reduced the risk of death by 15% (HR 0.85, 95% CI, 0.73-0.97). The 15-year cumulative incidence of death from ischemic or valvular heart disease was 0.2% (95% CI, 0.0-0.5) in right-sided and 0.7% (95% CI, 0.4-1.2) in left-sided patients.Interpretation: IMNI reduced distant metastasis and breast cancer mortality and improved OS in node-positive breast cancer patients, despite treatment with newer systemic therapies and 3D-based RT. This was found also in patients with limited nodal disease. The RT QA revealed some variation in dose coverage of the IMN, but overall a significantly higher IMN dose in right-sided patients in harmony with the aim of the trial. The gain from IMNI may be even higher with improved RT planning and delivery.¨