Abstract PS13-04: Frequent Intra-Tumoral Hypoxia in Pregnancy-Associated Breast Cancer
Authors: Bakhuis Carsten , Van Dooijeweert Carmen , Suelmann Britt , Westenend Pieter , Linn Sabine , Van der Wall Elsken , Van Diest Paul 
Published: May 2024

Abstract
Rationale:
Breast cancer is the most common malignancy in pregnant women, occurring in approximately 1:3000 pregnancies. Breast cancer diagnosed during pregnancy or after childbirth is also known as Pregnancy-Associated Breast Cancer (PABC). PABC is known for exhibiting several unfavorable prognostic tumor characteristics, such as an advanced tumor stage at diagnosis, high histologic grade and frequent hormone receptor negativity. Most probably, several interplaying mechanisms may promote the tumor progression and adverse clinical outcome of PABC. One of these mechanisms may be the presence of hypoxia, a relative state of low intra-tumoral oxygen levels which is a known marker of adverse outcome in breast cancer. However, the occurrence and prognostic consequences of the presence of intra-tumoral hypoxia in PABC have not been studied yet.
Methods:
We constructed a cohort with histopathological, clinical, and outcome data of patients diagnosed with breast cancer during pregnancy (PrBC) or within one year after childbirth (PPBC) in the Netherlands between 1988 and 2022. Next, tissue blocks of all patients were collected from the participating Dutch pathology laboratories. Using H&E stained slides of the tumor tissue blocks, we selected suitable donor sites for a tissue micro array (TMA). Slides from these TMAs were stained for three important hypoxia-associated proteins: glucose transporter-1 (Glut-1), carbonic anhydrase IX (CAIX) and hypoxia-inducible factor-1α (HIF-1α). Expression was scored by an expert breast pathologist blinded by clinicopathologic data.
Results:
For a total of 195 PrBC and PPBC patients, we were able to assess the expression of Glut-1, CAIX and HIF-1α on tumor cells. Patients had a median age of 33 years at diagnosis, whilst a large majority had a Bloom & Richardson grade III tumor (76%) with frequent hormone receptor negativity (50%). Expression of hypoxia-associated proteins was frequent, with 61% of the tumors expressing Glut-1, 30% expressing CAIX and 56% expressing HIF-1α. In total, 153 (78%) of the tumors expressed at least one of the hypoxia-associated proteins. We observed a significantly worse 5-year overall survival for patients with intra-tumoral hypoxia in comparison to patients without intra-tumoral hypoxia (70% vs. 90%, p=0.046).
Conclusions:
We show that the presence of intra-tumoral hypoxia in PABC is common, with 78% of tumors expressing at least one of the studied hypoxia-associated proteins. Importantly, patients with tumors overexpressing hypoxia-markers have a significantly worse survival. This shows that intra-tumoral hypoxia may be an important underlying carcinogenic mechanism in PABC, and might be a promising novel therapeutic target in this patient group.
Citation Format: Carsten Bakhuis, Carmen Van Dooijeweert, Britt Suelmann, Pieter Westenend, Sabine Linn, Elsken Van der Wall, Paul Van Diest. Frequent Intra-Tumoral Hypoxia in Pregnancy-Associated Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS13-04.