Short summary

High-risk breast cancer encounters tumors with non-resectable metastases to locoregional lymph nodes detected by FDG-PET/CT. Current clinical guidelines lack recommendations on handling of such lymph nodes, leaving several options available especially for radiotherapy after surgery. Therefore, this study aims to describe the clinical management of FDG-avid locoregional lymph nodes regarding radiotherapy treatment planning with long term follow-up to inform future clinical guidelines.

Rationale

Breast cancer is the leading cause of malignancy in women globally, with a worldwide both-sex incidence of 2,261,419 in 2020. The lifetime probability of developing breast cancer is one in eight women in the United States. High-risk breast cancer encounters breast cancer with large tumors and metastasis to locoregional lymph nodes, and these patients are at high risk of distant metastasis and later recurrence. Treatment for high-risk primary breast cancer often consists of a multi-modality approach according to the molecular subtype, e.g., neoadjuvant chemotherapy plus/minus anti-HER2 treatment and later surgery, radiotherapy, and endocrine therapy. Before initiating neoadjuvant treatment, additional imaging for distant metastasis is recommended in current clinical guidelines. Computed tomography (CT) plus a bone scan or 18F-fluoro-deoxy-glucose-positron emission tomography/computed tomography (FDG-PET/CT) are the most commonly used imaging modalities in this setting. FDG-PET/CT is superior in detecting distant metastasis of breast cancer but also leads to a migration of the initial TNM-stage, primarily due to the detection of metastasis in the infra- and supraclavicular and internal mammary lymph nodes (IMN). This stage migration affects the derived post-surgery radiotherapy treatment planning, including standard locoregional treatment plus/minus introducing an integrated- or sequential boost to involved non-resected locoregional lymph nodes. However, no clear recommendations on radiotherapy treatment planning, doses, and fractionation appear for PET-positive locoregional lymph nodes in current national or international guidelines. Therefore, this study aims to investigate the clinical management of non-resected PET-positive locoregional lymph nodes in women with primary breast cancer. This will be done by addressing the following objectives: i) distribution of non-resected PET-positive locoregional lymph nodes (i.e., infra- and supraclavicular, and IMN), ii) radiotherapy treatment planning of non-resected PET-positive locoregional lymph nodes, and iii) follow-up for the pattern of recurrence and survival estimates.

Description of the cohort

Patients with early breast cancer referred for an additional staging FDG-PET/CT between 1 January 2016 and 31 June 2023 in one of the institutions will be eligible for inclusion. Inclusion criteria: o Women aged 18 years or older o Biopsy-verified non-metastatic breast cancer o PET-positive locoregional lymph nodes (i.e., infra- and/or supraclavicular and/or IMN) Exclusion criteria: o Biopsy-verified other invasive cancer within five years of breast cancer diagnosis o Pregnancy Involved institutions: o Odense University Hospital o Vejle Hospital o Aarhus University Hospital o Aalborg University Hospital o Copenhagen University Hospital o Herlev-Gentofte Hospital

Data and biological material

Outcome measures will be: o Number, size, and location of PET-positive locoregional lymph nodes. o Additional examinations (biopsy, imaging, or other) o Medical oncology treatment o Pathological response to neoadjuvant treatment (complete versus non-complete response). o Radiotherapy treatment planning: irradiated volume (breast and lymph nodes), additional lymph node boost, doses, fractionation regimens, and organs at risk. o Follow-up: for the pattern of recurrence, invasive disease-free survival (iDFS), regional nodal recurrence-free survival (RRFS), and overall survival (OS).

Collaborating researchers and departments

Department of Oncology, OUH.

• Main supervisor: Marianne Vogsen, MD, PhD, associate professor.
• Project participant: Mette Holck Nielsen, MD, PhD.

Department of Nuclear Medicine, OUH.

• Co-supervisor: Malene Grubbe Hildebrandt, MD, professor.

Department of Clinical Research, University of Southern Denmark.

• Undergraduate student: Agnethe Langborg Rudbeck, Medical student.

Department of Oncology, AUH.

• Project participant: Birgitte Vrou Offersen, MD, PhD, professor.

Department of Oncology, AAUH.

• Project participant: Marie Louise Holm Milo, MD, PhD, associate professor.

Department of Oncology, Vejle Hospital.

• Project participant: Else Maae, MD, PhD.