Pregnancy-associated Breast Cancer: Tumor Infiltrating Lymphocytes TILting the Balance?

564 Background: Pregnancy-Associated Breast Cancer (PABC), which includes breast cancer diagnosed during pregnancy (PrBC) or postpartum (PPBC), is often more aggressive and diagnosed at more advanced stage compared to breast cancer in non-pregnant young women. The aggressive tumor growth in PABC may be influenced by the maternal shift towards immunotolerance during pregnancy, aimed at safely harboring the semi-allogenic fetus. Potentially, this shift allows cancer cells to evade immune detection. In recent years, the importance of stromal tumor-infiltrating lymphocytes (sTILs) as a marker of the anti-cancer immune response has become evident. Given the aforementioned relevance of immunotolerance in PABC development, we have evaluated the presence and prognostic importance of sTILs in PrBC and PPBC patients in this most extensive study to date. Methods: We assessed tumor tissues from the Dutch Pregnancy-Associated Breast Cancer Cohort, which includes PrBC and PPBC (≤1 year postpartum) patients diagnosed between 1988 and 2022. Whole slide images (H&E) of tumors from 200 patients were uniformly reviewed, and sTILs were scored according to international guidelines. Given the lack of previous sTIL cutoffs for PABC, a data-driven approach was chosen. Results: Our initial analysis revealed a clear survival benefit for a sTIL score of at least 20%. Therefore, our PrBC/PPBC patient group was divided into a “Low sTILs” ( < 20%, n = 153) and a “High sTILs” (≥20%, n = 47) group. High sTIL scores were associated with a higher histologic grade (89% grade III versus 73% in the low sTIL group, p = 0.043) and more frequent triple negativity (68% versus 43%, p = 0.021) Despite this more aggressive histopathology, higher sTILs were associated with a significantly better 5-year overall survival (OS) probability (94% versus 69%, p < 0.001). In a multivariable analysis, correcting for disease stage, intrinsic subtype and tumor grade, high sTIL scores remained a strong prognostic indicator in PABC (HR 7.3, 95% CI 2.24 – 23.9). In a subgroup analysis for triple negative disease only (n = 93), patients with a high sTIL score (n = 30) showed a better 5-year OS probability (93% versus 60%, p = 0.002), which also persisted in a multivariable analysis (HR 4.7, 95% CI 1.4 – 15.7). Conclusions: Despite the immunotolerance in pregnancy, this study demonstrates the presence and prognostic importance of sTILs in PABC. Importantly, patients with high sTILs (≥20%) had a markedly better prognosis despite having more aggressive disease characteristics, regardless of subtype. Therefore, sTILs may be an important prognostic indicator and may aid in selecting patients to forgo adjuvant systemic therapy, especially during pregnancy.