Abstract PS1-04: Tumor-infiltrating Lymphocytes (tils) and Response to Neoadjuvant Chemotherapy in Young Patients with Breast Cancer

Background: Increased TILs are associated with higher pathologic complete response (pCR) rates after NACT for breast cancer, but scant data exist in patients ≤ 40 years old, in whom age-related differences in host and tumor immune microenvironment may exist. We assessed the extent and composition of immune infiltration in breast tumors of young women undergoing NACT and correlated with clinicopathologic features and treatment response. Methods: Patients with stage I-III breast cancer who had NACT and available pre-treatment tumor tissue were identified from a prospective cohort study of women with breast cancer diagnosed at age ≤ 40 years. Multiplexed immunofluorescence was used to quantify cytotoxic T (CD8+), T helper (CD3+CD8-), T regulatory (Treg, FOXP3+CD3+), exhausted T (PD1+CD8+), and PDL1+ cells in stroma and tumor as a percentage value of positive cells. Univariate analyses tested associations of TIL levels (high vs. low, divided based on median) with clinicopathologic variables and compared TIL levels (continuous) between pCR and non-pCR cases. Logistic regression tested associations between TIL subtypes (continuous, per 10% increase) and pCR. Results: Among 194 patients, median age was 36 years (range 22-40 years), 14% were positive for BRCA1/2 mutations, and most had grade 3 (71%), > 2 cm (87%), node-positive (79%) tumors. Forty-one percent of tumors were hormone receptor (HR)-positive/HER2-negative, 33% HER2-positive/HR-positive or -negative, and 27% triple-negative. Sixty-one patients (31%) experienced pCR after NACT. Patients with recent pregnancies (≤ 5 years prior, n=80) had higher stromal infiltration of T helper (P=.020) and cytotoxic T (P=.002) cells as well as higher intratumoral infiltration of cytotoxic T (P=.001), Treg (P=.018) and exhausted T (P=.049) cells compared to those who were nulliparous (n=52), pregnant at diagnosis (n=7) or pregnant > 5 years prior (n=24). BRCA1 mutations (n=19) were associated with high levels of exhausted T cells in stroma (P=.021) and tumor (P=.048). Grade 3 tumors (n=137) had higher levels of T helper cells in stroma (P=.030) and tumor (P=.010). Triple-negative (n=52) and HER2-positive (n=63) tumors had higher stromal Treg infiltration (P=.046). Triple-negative and stage III tumors (n=66) were associated with high levels of PDL1+ cells in stroma (P=.033) and tumor (P=.005), respectively. No differences in TILs were seen according to age, race, ethnicity or histological subtype. Patients with pCR had greater stromal Treg (P=.0189), intratumoral T helper (P=.0043) and intratumoral PDL1+ cell infiltration (P=.0372). Increased stromal Tregs was predictive of pCR, controlling for breast cancer stage, grade and subtype (OR 1.63, 95% CI 1.12-2.28, P=.011). Increased levels of all intratumoral TIL subtypes was predictive of pCR, with odds ratios ranging from 1.14 (95% CI 1.02-1.29, P=.026) for PDL1+ cells to 2.02 (95% CI 1.31-3.12, P=.002) for Tregs for each 10% increment, controlling for breast cancer stage, grade and subtype. Conclusions: The distribution of TIL subtypes in young patients’ breast tumors pre-treatment varied according to recency of pregnancy, BRCA1/2 mutation status and tumor characteristics. High levels of most TIL subtypes was associated with improved response to NACT, independent of breast cancer subtype. The relationship between TILs and pCR in young women appears similar to that in older women, suggesting that tumors of younger and older patients may not be fundamentally different when analyzed according to clinically relevant biologic features. Characterization of immune subpopulations could help refine the predictive value of TILs in young patients with breast cancer, who may benefit from individualized escalated and de-escalated treatment strategies. Citation Format: Megan Tesch, Yaileen D. Guzmán-Arocho, Laura C. Collins, Yujing J. Heng, Shoshana M. Rosenberg, Kathryn J. Ruddy, Rulla Tamimi, Lidia Schapira, Jeffrey Peppercorn, Virginia Borges, Steven E. Come, Craig Snow, Eric P. Winer, Elizabeth A. Mittendorf, Ann H. Partridge. Tumor-infiltrating lymphocytes (TILs) and response to neoadjuvant chemotherapy in young patients with breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr PS1-04.