Maria Marcela Monteiro

e12629 Background: Triple-negative breast cancer (TNBC) prognosis is significantly influenced by tumor-infiltrating lymphocytes (TILs), but the lack of validated cutoff values has limited their clinical applicability. In the era of neoadjuvant pembrolizumab plus chemotherapy (P+CT) as a new standard of care, the role of TILs as predictors of response to chemoimmunotherapy remains uncertain. Methods: This study aimed to assess TILs as predictors of pathologic complete response (pCR) within the Neo-Real study, a multicenter, real-world data investigation on neoadjuvant P+CT in TNBC. TILs were evaluated using the standardized methodology of the International TILs Working Group. Logistic regression and receiver operating characteristic (ROC) curve analysis were performed to evaluate the predictive ability of TILs expression and multivariable models for pCR. Results: The analysis included 128 patients (pts) treated with neoadjuvant P+CT (68% stage II, 26% stage III). The proportion of pts in each TILs’ category and results of ROC curve analysis are presented in the Table. A cutoff value of 10% demonstrated the highest accuracy in predicting pCR, while a high specificity was observed at a cutoff value of 50%. Thus, the probability of residual disease if TILs ≥ 50% is considerably low. Incorporating categorized clinical and pathological variables, a multivariable logistic regression model, using TILs (≥ 10% vs < 10%), Ki67 (≥ 50% vs < 50%), and tumor stage (III vs II), exhibited the highest AUC (0.688) for predicting pCR. Conclusions: Our study underscores the predictive value of TILs for pCR in TNBC following neoadjuvant P+CT. The cutoff value of ≥ 50% identified patients with a very high probability of pCR. The results reinforce TILs’ use as a biomarker for treatment de-escalation, especially for pts with TILs ≥ 50%. Further enhancement of TILs' predictive potential may be achieved through multivariable models. [Table: see text]

e12618 Background: Triple-negative breast cancer (TNBC) is the most immunogenic subtype and is highly prevalent among patients (pts) with germline BRCA1/2 mutations (gBRCAm). Regardless of mutation status, the current standard treatment for early-stage TNBC is chemotherapy combined with pembrolizumab, as per the KEYNOTE-522 protocol. Methods: Data were collected from pts diagnosed with early-stage TNBC treated according to the KEYNOTE-522 regimen at ten cancer centers from July 2020 to December 2024. Epidemiological data and treatment outcomes of pts with gBRCAm were compared to those with BRCA wild-type/unknown (BRCAwt). Results: A total of 413 pts were analyzed, of whom 320 (82%) underwent germline testing; 49 (12.7%) had a gBRCAm, including 45 (91%) with BRCA1 and 4 (9%) with BRCA2 mutations. Pts with gBRCAm were younger (median 39 vs. 44 years, P<0.001) and more likely to be premenopausal (80.8% vs. 65.6%, P=0.045) and have grade 3 tumors (91% vs. 80%, P=0.214) than BRCAwt pts. Stage II disease was the most common in both groups (71.4% vs. 70%, P=0.315). Regarding treatment, gBRCAm pts were more frequently treated with dose-dense AC (doxorubicin and cyclophosphamide) (66% vs. 54%, P=0.160) and underwent mastectomy more often (93.9% vs. 35.9%, P=0.001). Only 2% of gBRCAm pts experienced disease progression during neoadjuvant therapy compared to 5% of BRCAwt pts (P=0.491).Pathological complete response (pCR; ypT0-Tis ypN0) rates were 73% in gBRCAm pts compared to 61% in BRCAwt pts (P=0.114). Residual cancer burden (RCB) 0-1 occurred in 83.7% vs. 76.6% (P=0.345). Subgroup analysis by disease stage revealed pCR rates of 74.3% in stage II gBRCAm pts versus 65.2% in BRCAwt pts (P=0.334), and 72.7% in stage III gBRCAm pts compared to 45.3% in BRCAwt pts (P=0.113).Grade 3 or higher adverse events (AEs) occurred in 50% of gBRCAm pts versus 34.9% of BRCAwt pts (P=0.055), with more frequent neutropenia (32.6% vs. 19.5%, P=0.041), diarrhea (6.1% vs. 1.6%, P=0.079), and immune-related AEs (12.2% vs. 7.4%, P=0.259). There were no significant differences in drug discontinuation rates due to toxicity (28% vs. 22%, P=0.327). Conclusions: Pts with gBRCAm exhibited high pCR rates with the KEYNOTE-522 regimen, achieving pCR rates over 70% even in stage III disease. Further research is needed to optimize treatment strategies in this population, including potential de-escalation approaches.

e13072 Background: Hormone-positive breast cancer is prone to late recurrence and is biologically heterogeneous. The advent of selective estrogen receptor degraders (SERDs), such as fulvestrant, has improved treatment for metastatic disease. However, resistance to hormones and ESR1 mutations continues to impede disease control. Emerging drug combinations aim to address these obstacles while avoiding more systemic chemotherapy. We analyzed the efficacy of novel oral SERDs combined with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in recurrent or metastatic hormone-positive breast cancer. Methods: We searched for randomized clinical trials that reported the use of new oral SERDs combined with CDK4/6 inhibitors in patients with recurrent or stage IV breast cancer, using the PubMed, Cochrane, and Embase databases up to December 2025. The primary efficacy endpoints were Objective Response Rate (ORR), Clinical Benefit Rate (CBR), and Progression-Free Survival (PFS) in both intention-to-treat and ESR1 mutation-positive patients. Considering safety, we assessed treatment-related adverse events (TRAEs) by any grade and grade 3. Statistical analysis was performed using R software. We analysed heterogeneity with I² statistics and pooled proportions using a random-effects model. Results: We included six prospective studies with 1178 patients that met eligibility criteria. The pooled median PFS was 10.09 months (95% CI 6.79 - 15, I² = 88.7%), while subgroup analysis of patients in second-line endocrine therapy has a similar PFS of 10.26 months (95% CI 5.80 - 18.17, i² = 91,1%). The ORR was 21.90% (95% CI 13.37- 33.77, I² = 84.5%) and CBR 68.97% (95% CI 53.33-81.22, I² = 92.3%). Patients harboring ESR1 mutations present a median PFS of 11.61 months (95% CI 7.81-17.21, I² 83.5%). TRAEs by any grade were 89.17% (95% CI 66.67- 97.13, I2 = 95.1%), while grade 3 were 49.42% (95% CI 31.88-67.10, I2 = 88.6%). Conclusions: The combination of new oral SERDs and CDK 4/6 inhibitors in hormone-positive breast cancer constitutes a promising and effective strategy for metastatic disease control with manageable toxicity. Addressing the ESR1 mutational profile is crucial to optimizing the impact of this therapeutic approach.