NCCN guidelines recommend genetic testing for all triple-negative breast cancer (TNBC) patients aged ≤60 years. However, due to the lack of prospective information in unselected patients, these guidelines are not uniformly adopted by clinicians and insurance carriers. The aim of this study was to determine the prevalence of BRCA mutations and evaluate the utility of NCCN guidelines in unselected TNBC population. Stage I–IV TNBC patients were enrolled on a prospective registry at academic and community practices. All patients underwent BRCA1/2 testing. Significant family history (SFH) was defined >1 relative with breast cancer at age ≤50 or ≥1 relative with ovarian cancer. Mutation prevalence in the entire cohort and subgroups was calculated. 207 TNBC patients were enrolled between 2011 and 2013. Racial/ethnic distribution: Caucasian (80 %), African–American (14 %), Ashkenazi (1 %). Deleterious BRCA1/2 mutations were identified in 15.4 % (32/207) of patients (BRCA1:11.1 %, BRCA2:4.3 %). SFH reported by 36 % of patients. Mutation prevalence in patients with and without SFH was 31.6 and 6.1 %, respectively. When assessed by age at TNBC diagnosis, the mutation prevalences were 27.6 % (≤50 years), 11.4 % (51–60 years), and 4.9 % (≥61 years). Using SFH or age ≤50 as criteria, 25 and 34 % of mutations, respectively, were missed. Mutation prevalence in patients meeting NCCN guidelines was 18.3 % (32/175) and 0 % (0/32) in patients who did not meet guidelines (p = .0059). In this unselected academic and community population with negligible Ashkenazi representation, we observed an overall BRCA mutation prevalence rate of 15.4 %. BRCA testing based on NCCN guidelines identified all carriers supporting its routine application in clinical practice for TNBC.

Purpose: Addition of carboplatin (Cb) to anthracycline chemotherapy improves pathologic complete response (pCR), and carboplatin plus taxane regimens also yield encouraging pCR rates in triple-negative breast cancer (TNBC). Aim of the NeoSTOP multisite randomized phase II trial was to assess efficacy of anthracycline-free and anthracycline-containing neoadjuvant carboplatin regimens. Patients and Methods: Patients aged ≥18 years with stage I–III TNBC were randomized (1:1) to receive either paclitaxel (P) weekly × 12 plus carboplatin AUC6 every 21 days × 4 followed by doxorubicin/cyclophosphamide (AC) every 14 days × 4 (CbP → AC, arm A), or carboplatin AUC6 + docetaxel (D) every 21 days × 6 (CbD, arm B). Stromal tumor-infiltrating lymphocytes (sTIL) were assessed. Primary endpoint was pCR in breast and axilla. Other endpoints included residual cancer burden (RCB), toxicity, cost, and event-free (EFS) and overall survival (OS). Results: One hundred patients were randomized; arm A (n = 48) or arm B (n = 52). pCR was 54% [95% confidence interval (CI), 40%–69%] in arm A and 54% (95% CI, 40%–68%) in arm B. RCB 0+I rate was 67% in both arms. Median sTIL density was numerically higher in those with pCR compared with those with residual disease (20% vs. 5%; P = 0.25). At median follow-up of 38 months, EFS and OS were similar in the two arms. Grade 3/4 adverse events were more common in arm A compared with arm B, with the most notable differences in neutropenia (60% vs. 8%; P < 0.001) and febrile neutropenia (19% vs. 0%; P < 0.001). There was one treatment-related death (arm A) due to acute leukemia. Mean treatment cost was lower for arm B compared with arm A (P = 0.02). Conclusions: The two-drug CbD regimen yielded pCR, RCB 0+I, and survival rates similar to the four-drug regimen of CbP → AC, but with a more favorable toxicity profile and lower treatment-associated cost.

513 Background: Addition of pembrolizumab to anthracycline-taxane-platinum chemotherapy improves pathologic complete response (pCR) and event free survival (EFS) in TNBC. Aim of this study was to assess the efficacy of the anthracycline free neoadjuvant regimen of pembrolizumab plus carboplatin plus docetaxel (Cb+D) in TNBC. Methods: In this multicenter study, eligible patients with stage I-III TNBC received carboplatin (AUC 6) + docetaxel (75 mg/m2) + pembrolizumab (200 mg) every 21 days x 6 cycles. The primary endpoint was pCR (no evidence of invasive tumor in breast and axilla). Secondary endpoints were residual cancer burden (RCB), EFS, toxicity, and immune response biomarkers. RNA isolated from pretreatment tumor tissue was subjected to next generation sequencing. Samples were classified as DNA Damage Immune Response (DDIR) signature and DetermaIO signature positive/negative using predefined cutoffs. Evaluation of stromal tumor infiltrating lymphocytes (sTILs) was performed using standard criteria. Results: 117 patients were enrolled from September 2018 to January 2022. 18% were African American, 39% had node positive disease, 88% had stage II/III disease and 15% had ER/PR 1-10%. Pathologic response information is available for 105 patients. pCR and RCB 0+1 rates were 60% (95% CI 51%-70%) and 71% (95% CI 62%-80%), respectively. Treatment related adverse events led to discontinuation of any trial drug in 12% of patients. Immune adverse events were observed in 28% of patients (Grade ≥3=6%). 47% of patients had sTILs ≥30%, 48% were DetermaIO positive, and 61% DDIR positive. The table describes the impact of these biomarkers on pCR and RCB. The areas under the prediction curve (AUC) for pCR were 0.660, 0.709, and 0.719 for DDIR, sTILs, and DetermaIO respectively. At a median follow up of 21 months, 2-year EFS is 88% in all patients; 98% in pCR group and 82% in no pCR group. Conclusions: Neoadjuvant pembrolizumab plus Cb+D regimen yields pCR of 60% and 2-year EFS of 88% in the absence of adjuvant pembrolizumab. The regimen was well tolerated, and no new toxicity signals were noted. Immune enrichment identified by sTILs or DetermaIO signature was associated with high pCR rates approaching or exceeding 80%. PD-L1 and additional biomarker analyses are ongoing. Clinical trial information: NCT03639948. [Table: see text]

505 Background: Ribociclib (R) + letrozole (L) is superior to L in metastatic breast cancer (BC). Preoperative endocrine prognostic index (PEPI) score 0 after neoadjuvant endocrine therapy (NET) is associated with low risk of relapse without chemotherapy in ER+ BC. On-therapy change in Ki-67 predicts adjuvant recurrence. FELINE is a biomarker-based multicenter randomized trial comparing changes in Ki-67 and PEPI between L+ Placebo (P) & L+R. Methods: Postmenopausal women with >2 cm or node+ ER+ HER2- BC were randomized 1:1:1 between L+P, L+R 400 mg continuous dose (Rc) and L+R 600 mg, 3 weeks on/1 week off - intermittent dose (Ri). Treatment was continued for six 28-day cycles. Core biopsies, blood samples were obtained at baseline, Day 14 cycle 1 (D14C1), and surgery. Clinical measurement, mammogram and US were obtained at baseline, surgery; MRI at baseline, week 8. Primary endpoint was rate of PEPI score 0 between L+P and L+R (i+c combined). Other endpoints were change in centrally performed Ki-67, complete cell cycle arrest (CCCA): Ki-67 <2.7%, clinical/imaging response, and difference in response & toxicity between the two R (Rc and Ri) arms. Results: From 2/2016 to 8/2018, 120 women were enrolled at 9 US centers. Thirty-eight were randomized to L+P and 82 to L+R groups (41 in Ri and Rc). Treatment groups were balanced at baseline. PEPI score of 0 was equal (25%) in L+P & L+R groups. CCCA at D14C1 was observed in 52% vs. 92% in L+P, L+R respectively (p < 0.0001). CCCA at surgery was observed in 63.3% vs. 71.4% in L+P, L+R respectively (p = NS). A significant increase in Ki-67 was observed between D14C1 and surgery in 66% vs. 33% in L+R, L+P respectively (p = 0.006). There was no difference in clinical, mammographic, US or MRI response between L+P and L+R. CCCA at D14C1 and surgery was similar in Ri & Rc arms. Grade >3 AEs were observed in 4 (10%) patients in L+P, 23 (56%) in L+Ri, 19 (46%) in L+Rc arms. Conclusions: Addition of R to L as NET did not result in more women with a PEPI score of 0. At D14C1 twice as many women on L+R had CCCA compared to L+P (92% vs 52%). However, significantly more women on L+R had increased proliferation between D14C1 and surgery , resulting in similar CCCA at surgery. Correlative studies are being performed to determine mechanisms of on-therapy acquired resistance to ribociclib. Continuous and intermittent doses of R have similar efficacy, toxicity. Clinical trial information: NCT02712723 . [Table: see text]

No abstract