Triple Negative Breast Cancer Pts Research Articles

A-BRAVE trial: A phase III randomized trial with avelumab in early triple-negative breast cancer with residual disease after neoadjuvant chemotherapy or at high risk after primary surgery and adjuvant chemotherapy.

LBA500 Background: Prognosis of pts with early triple negative breast cancer (TNBC) is still poor and new effective treatments are needed. TNBC is the most immunogenic BC subtype, and this may account for sensitivity to immune checkpoint inhibitors. The A-BRAVE trial was designed to evaluate the efficacy of avelumab, an anti PD-L1 antibody, as adjuvant treatment for pts with early TNBC at high risk. Methods: This is a phase III, multicentric, randomized adjuvant study comparing 1 year of treatment with the anti PD-L1 avelumab vs observation for TNBC pts considered at high risk of relapse. Pts were enrolled after they completed standard treatment with curative intent including surgery and neoadjuvant/adjuvant chemotherapy. High risk was defined as: 1) invasive residual disease (breast and/or nodes) after neoadjuvant chemotherapy (Stratum A), 2) >pN2/any pT, pN1/pT2, or pN0/pT3 after primary surgery (Stratum B). Pts were randomly assigned (1:1, balanced for strata A and B) to Avelumab 10 mg/kg I.V. q2w for 1 year or observation. Co-primary endpoints were disease free survival (DFS) in the total population and in Stratum A. 474 pts were needed to detect, in the total population, an improvement from 60% to 73.6% 3-year DFS rate (HR 0.6; 90% power, 1-sided test, alfa 2%). 172 DFS events were required to perform the event-driven analysis. Assuming a proportion of 70-80% pts enrolled in Stratum A, the expected power to detect an HR 0.6 at alpha allocated in this subgroup is 70-79%. Overall survival was a secondary endpoint. Results: From June 2016 to October 2020, 477 pts were randomly assigned from 64 Italian and 6 UK centers. 11 pts (3 avelumab, 8 control) withdrew consent immediately after randomisation and are excluded from further analyses. 378 pts entered Stratum A (83%), of whom 99 (57 avelumab, 42 control) received further chemotherapy after surgery prior to enrollment in the trial. Efficacy results for the two co-primary DFS endpoints and the secondary OS endpoints are reported in the table. Conclusions: One year adjuvant avelumab versus control does not significantly improve DFS in high-risk TNBC patients. Nevertheless, the secondary enpoind OS was significanlty improved with avelumab vs control. RFS and DMFS will also be reported. A centralised collection of tumor tissue, plasma and feces has been performed and will allow a number of correlative studies. Clinical trial information: NCT02926196 . [Table: see text]

Dose escalation and expansion results from the phase I study of F0024, a trophoblast cell-surface antigen 2 (TROP2) antibody-drug conjugate (ADC), in patients (pts) with advanced solid tumors.

e13131 Background: F0024 is an antibody-drug conjugate (ADC) targeting Trop-2, an intracellular calcium signaling transducer overexpressed on many epithelial tumors, for delivery of SN-38, the active metabolite of irinotecan. We assessed its safety and efficacy in patients with advanced solid tumors, mainly in triple negative breast cancer (TNBC). Methods: PTs with unresectable solid tumors refractory to/relapsed from standard treatment received F0024 on days 1 and 8 of 21-day treatment cycles. Primary objectives include maximum tolerated dose (MTD) identification, safety, and tolerability and secondary objectives include efficacy, pharmacokinetics, and incidence of anti-drug antibodies against F0024. Pts were eligible regardless of TROP2 level. Results: As of October 8, 2023, 62 pts were treated with≥1 dose of F0024. 21 pts were treated during dose escalation at 2.5 (n = 1), 5.0 (n = 3), 7.5 (n = 3), 10 (n = 4), 12 (n = 8), and 15 (n = 2) mg/kg and 41 pts with TNBC were treated in dose expansion at 10.0 (n = 30) and 12.0 (n = 11) mg/kg. 32 pts (51.6%) discontinued (20 (32.2%) due to disease progression per RECIST v1.1). Treatment emergent adverse events (TEAEs) regardless of causality were reported in 61 of 62 pts (98.4%; 34 pts [54.8%] experienced ≥grade 3, 9 pts [14.5%] had serious adverse events). Treatment related adverse events (TRAEs) were reported in 61 of 62 pts (98.4%; 32 pts [51.6%] experienced ≥grade 3, 4 pts [6.5%] had serious adverse events). The most common grade 3 TRAE were neutropenia (45.2%), leukopenia (33.9%), febrile neutropenia (4.8%), anemia (4.8%), and maculo-papular rash (4.8%). A total of 17 responses have been observed at the dose of 5.0 mg/kg or greater. 34 TNBC pts were dosed at 10 and 19 were dosed at 12 mg/kg with exposure to a median of 11.5 (1.0-26.0) and 4.0 (1.0-21.0) doses. 11 partial responses were achieved in 29 efficacy-evaluable TNBC pts at 10 mg/kg leading to an overall response rate (ORR) of 37.9% (95% CI 20.7% - 57.7%). The disease control rate of 10 mg/kg is 79.3% (95% CI 60.3%-92.0%). 5 escalation pts and 25 expansion pts remain on trial. Updated trial details/results will be presented. Conclusions: In this first-in-human study of F0024, treatment was generally well tolerated and MTD was not yet reached up to 12 mg/kg. F0024 demonstrated encouraging preliminary antitumor activity in heavily pretreated TNBC pts, especially in 10 and 12 mg/kg. Clinical trial information: NCT05174637 .

Immune-phenotyping of peripheral blood mononuclear cells from patients with early triple-negative breast cancer: Identification of a systemic immunosuppressive CD3+ CD4+ CD39+ Treg subset.

3040 Background: Cells of the immune system and malignant cells interact in the tumor microenvironment, influencing response to treatment and survival. The current study was undertaken to assess the prevalence of these immune cells systemically in patients with early triple-negative breast cancer (TNBC). Methods: Multi-parameter flow cytometry was used to examine the percentages and phenotypes of cytotoxic T cells, natural killer (NK) cells, monocyte subsets, and regulatory T cell (Treg) subsets in the peripheral blood of 19 TNBC patients (pts) and 10 controls (cnt). Multicolor flow cytometry was carried out using DURAClone IM phenotyping (basic and Treg tubes) with a CytoFLEX Flow Cytometer (Beckman Coulter, California, USA), and data analyzed with FlowJo v 10.10.0 software (BD Life Sciences, USA). The Mann-Whitney U-test was used to compare non-parametric data where appropriate. Results: Significant increases in the percentages of immunosuppressive CD3+ CD4+ CD39+ Tregs cells in the setting of a significant decrease of CD19+ B cells were observed in pts with TNBC (Table).Tumour size, nodal status, age and ki-67 did not correlate with the percentages of any type of circulating immune cell. Conclusions: TNBC is associated with severe immunosuppression. In this context, percentages of circulating CD19+ B cells were significantly lower, while CD3+ CD4+ CD39+ Tregs were significantly higher in early TNBC pts. The peripheral blood immunome of TNBC pts identified a subset of immunosuppressive Tregs. A study is ongoing to identify the prognostic and predictive values of this systemic subset of Tregs for pCR in early TNBC pts undergoing neoadjuvant chemotherapy. [Table: see text]

Impact of peridiagnostic genetic counseling and germline testing on treatment decisions for patients with triple negative breast cancer undergoing pembrolizumab-chemotherapy neoadjuvant approach.

e12633 Background: Triple negative breast cancer (TNBC) has been globally associated with a high risk of carrying pathogenic or likely pathogenic (P/LP) variants in germline breast cancer (BC) susceptibility genes (BCSG). Immunotherapy- based Neoadjuvant (pembro-NA) treatment is the preferred approach for localized, T2 or node positive TNBC. To the best of our knowledge, information about peridiagnostic genetic counseling (PGC), germline status and their impact on patients (pts) undergoing this treatment approach has not been reported yet. Our aim was to describe the feasibility and impact of PGC in TNBC pts treated with pembro-NA and to compare clinical benefits between carriers and wild type (WT) pts in a real- world (RW) setting. Methods: Consecutive, localized TNBC pts who received pembro-NA were enrolled, between March 2022 and August 2023 in a private Argentinian institution. Informed consent was obtained, and medical information collected from medical records and an institutional GC registry. Clinical benefit in terms of pathological complete response (pCR) was analyzed according to BCSG status. Univariate analyses, including chi-square, Fisher and Wilcoxon tests were performed when appropriate. p<0.05 was considered for statistical significance. Results: 47 pts were ascertained. 36.5% (15/41) tested positive for BCSG: 93% (14/15) for BRCA1-2 genes (gBRCA+). No differences were observed in pts ages, with medians of 45 years [IQR 40-50.5] vs 40 [IQR 35-48] among non-carriers versus carriers, respectively (p=0.56). Also, stage at presentation was similar for both subgroups (II: 77.8% vs 60%, III: 14.8% vs 33.3; p=0.37). PGC outcomes: 1/47 (2%) was previously diagnosed as BRCA1 positive (gBRCA+), 1/47 (2%) died before PGC assessment; 85% (40/47) were assessed locally; 64% (30/47) revealed a positive cancer family history; 93% (38/41) were tested through multi-gene panel testing. Median time from diagnosis to first GC appointment was 11.4 weeks (wk) and to disclosure of genetic results by a geneticist or oncologist was 13 wk. Treatment outcomes: 81% (38/47) had completed pembro-NA; one (2%) progressed in the WT group. pCR was achieved in 78.9% (30/38), with no differences between groups (p=0.46). Olaparib or capecitabine were added in pts that did not achieve pCR according to gBRCA status. Notably, 73% carriers versus 37.5% WT pts underwent risk-reducing bilateral mastectomy (p=0.0304). Conclusions: PGC is feasible in a RW scenario of limited resources such as in Argentina. We found a high rate of carriers, mostly gBRCA+, in which surgical decisions and post-NA treatments were determined considering germline status findings. Although efficacy differences between gBRCA+ and WT were not found, further research and data on long-terms outcomes are needed to assess comparative results.

Real-world immune-related adverse events in patients with early triple negative breast cancer who received pembrolizumab.

1099 Background: The addition of pembrolizumab to chemotherapy (KEYNOTE-522 regimen) in high risk early triple negative breast cancer (TNBC) has improved clinical outcomes. However, this treatment can result in immune-related adverse events (irAEs) involving any organ and in some cases, life-long toxicities or even death. This retrospective study describes real-world patterns of irAEs in patients (pts) with early TNBC who received pembrolizumab at two academic centers. Methods: We evaluated irAEs in pts with stage II-III TNBC from MD Anderson Cancer Center and Lyndon B Johnson diagnosed between January 2018 and May 2023 who received neoadjuvant pembrolizumab plus chemotherapy. We excluded those enrolled on clinical trials. We utilized ASCO irAE and CTCAE v5 guidelines for toxicity grading. Logistic regression assessed the effect of clinical variables on irAEs, adjusting for covariates. Results: We identified 233 pts with a median age of 51 ± 12 years; 62% with stage II and 35% with stage III TNBC; 25% were Hispanic/Latino, 21% non-Hispanic Black and 42% were non-Hispanic White. In total, 80 pts (34%) developed 100 separate irAEs (94 with definite and 6 with possible/probable attribution). The most common irAEs were endocrine (52%) followed by gastrointestinal (23%). Grade ≥ 3 irAE occurred in 26 instances, with the most common being gastrointestinal (13 instances). A fatal irAE occurred in 2 pts where both were colitis. A total of 26 irAEs resulted in hospitalization, 45 required systemic steroids, and 15 required additional immunosuppressive therapy. Most (66) irAEs were unresolved at last follow up, although the majority had improved to grade 1 (37/66) and 32 patients discontinued pembrolizumab early due to irAEs. No clinical factor (race, stage, tumor grade, age, body mass index) was associated with development of an irAE. Conclusions: In this real-world diverse population, we identified a similar rate and severity of irAEs as reported in the KEYNOTE-522 trial. Hospitalizations occurred in 26% of irAEs while most developed persistent immune toxicity. Gastrointestinal irAEs were more common compared to KEYNOTE-522 reported data. Research is needed to better predict and mitigate the burden of irAEs and to improve the long-term survivorship care of pts with early TNBC pts who receive pembrolizumab. [Table: see text]

9MW2821, a nectin-4 antibody-drug conjugate (ADC), in patients with advanced solid tumor: Results from a phase 1/2a study.

3013 Background: 9MW2821 is a monoclonal ADC that delivers monomethyl auristatin E to cells expressing Nectin-4. Nectin-4 is an adhesion molecule that highly expressed in variety of solid tumors, especially urothelial cancer (UC), cervical cancer (CC), esophageal cancer (EC) and breast cancer. Here we report the updated safety and efficacy data of 9MW2821. Methods: 9MW2821 was administered by intravenous infusion at doses of 0.33-1.5mg/kg on days 1, 8 and 15 of each 28-day cycle. The study included dose escalation, dose expansion and cohort expansion period which included UC, CC, EC, triple negative breast cancer (TNBC) and other Nectin-4 positive solid tumors that progressed after ≥1 systemic treatments (Tx). Primary objectives were assessment of safety and preliminary efficacy. Results: As of Jan 15, 2024, 260 patients (pts) were enrolled with doses ranging from 0.33 to 1.5mg/kg. Only 1 out of 6 pts in 1.5mg/kg group had dose limiting toxicity (grade 4 neutropenia lasted more than 5 days). The maximum tolerated dose was not reached up to 1.5mg/kg and the RP2D was selected as 1.25mg/kg for tolerance. 240 pts were enrolled at dose of 1.25mg/kg. The most common TRAEs of 1.25mg/kg dose group (≥20%, all grade/≥5%, ≥G3) were white blood cell (WBC) count decreased (50.8%, 23.3%), neutrophil count decreased (46.3%, 27.9%), anemia (43.8%, 8.3%), aspartate aminotransferase increased (42.1%, 2.9%), alanine aminotransferase increased (35.4%, 2.1%), asthenia (32.1%, 2.9%), rash (30.0%, 5.0%), decreased appetite (28.8%, 1.3%), nausea (26.7%, 0%), hyperglycemia (25.4%, 2.1%), platelet count decreased (24.2%, 4.6%), alopecia (24.2%, 0%), hypoaesthesia (22.5%, 1.7%), constipation (21.3%, 0%), vomiting (20.9%, 1.3%), hypertriglyceridemia (20.4%, 2.1%), gamma-glutamyltransferase increased (15.8%, 5.4%). Among 190 pts treated with 9MW2821 at 1.25mg/kg or above and reached tumor assessment, objective response rate (ORR) and disease control rate (DCR) was 35.3% and 78.4%, respectively. 37 UC pts, 45 CC pts, 27 EC pts and 16 TNBC pts were enrolled at 1.25mg/kg and evaluable for tumor assessment. Median prior lines of Tx were 2 (range, 1-4). All UC, 51% CC and 93% EC pts progressed after platinum-based chemotherapy and immune checkpoint inhibitors, respectively. Objective responses were also observed in pts with other solid tumor types. Conclusions: The data indicated encouraging efficacy of 9MW2821 in advanced UC, CC, EC and TNBC. 9MW2821 is the first Nectin-4 targeting ADC showed antitumor activity in patients with CC, EC and TNBC. The safety profile showed adequate tolerability. Clinical trial information: NCT05216965 . [Table: see text]

Non-basal subtype defined by FOXC1 expression as an independent predictor of capecitabine efficacy in the triple negative breast cancer GEICAM/2003-11_CIBOMA/2004-01 trial.

516 Background: In a prespecified correlative analysis of the GEICAM/2003-11_CIBOMA/2004-01 phase III clinical trial (CIBOMA trial), PAM50 non-basal status identified triple-negative breast cancer (TNBC) patients (pts) most likely to benefit from adjuvant capecitabine (cap). FOXC1 cell plasticity/metastasis transcriptional driver assessment by standardized Veresca FOXC1 Immunohistochemistry (IHC) BC test (Veresca) has shown rigorous capacity to identify basal-like breast cancer (BLBC) subtype throughout TNBC cohorts. We sought to explore the concordance of BLBC identification by FOXC1 with PAM50 molecular subtyping and its prognostic/predictive value in the CIBOMA trial (NCT00130533). Methods: We analyzed FOXC1 expression (Veresca, Onconostic Technologies) and the Ki-67 Antigen MIB-1 (Dako) by IHC on tumors from 705 TNBC pts randomized to maintenance with cap (357, 51%) vs observation (obs) (348, 49%) after standard (neo)adjuvant chemotherapy (CT). Veresca score (VFOXC1) was defined as % of tumor cells with positive nuclear staining (Proportion Score 0-5) plus staining intensity (Intensity Score 0-3). BLBC subtyping by Veresca (cutoff ≥4) and PAM50 signature (Nanostring) were compared using ROC analysis and Kappa index (KI). Ki67 ≥20% cutoff was applied. Cox regression models were assessed to predict DRFS (primary endpoint), DFS and OS (secondary endpoints). Results: VFOXC1≥4 identified 460 (65%) BLBC pts in this CIBOMA trial cohort (229 (49.8%) treated with cap, and 231 (50.2%) in obs). VFOXC1 detection was not associated with any clinicopathological characteristic. VFOXC1 expression significantly correlated with PAM50 BLBC subtyping (ROC analysis AUC 0.874, KI 0.43) but moderately with IHC subtyping (AUC 0.548). VFOXC1 BLBC subtype was not associated with DRFS (HR=0.94; 95%CI 0.68-1.30; p=0.713) in the entire cohort. However, VFOXC1 non-BLBC subtype was a strong independent predictor of cap benefit for DRFS (univariate analysis, interaction p-value p=0.117; HR=0.53; 95%CI 0.31-0.90; p=0.019; multivariate analysis, HR=0.44; 95%CI 0.25–0.76; p=0.003). This predictive effect of VFOXC1 non-BLBC on cap benefit was also confirmed at DFS (HR=0.47; 95%CI 0.28–0.78; p=0.003) and OS (HR=0.48; 95%CI 0.24–0.96; p=0.038), and was independent of Ki67 proliferation status (multivariate DRFS; Ki67<20%, HR=0.41; 95%CI 0.20-0.82; p=0.012; Ki67≥20%, HR=0.31; 95%CI 0.10-0.97; p=0.045). VFOXC1 non-BLBC subtype had no association with clinical outcome in obs arm. Conclusions: In the CIBOMA TNBC trial, the non-BLBC definition by a single biomarker (FOXC1 Veresca) provided prognostic and predictive value of cap benefit after (neo)adjuvant CT, corroborating our previous findings by PAM50 and IHC non-BLBC subtyping. This is a pragmatic option to effectively apply findings from this trial in the real-world setting. Clinical trial information: NCT00130533 .

Abstract PO5-13-08: Impact of systemic inflammation markers in response to neoadjuvant pembrolizumab and chemotherapy in triple-negative breast cancer - a retrospective analysis

Abstract Background: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment landscape for triple-negative breast cancer (TNBC). Systemic inflammation has been linked to cancer development and overall poor outcomes. Routine blood parameters have been investigated as potential inflammatory biomarkers in patients (pts) with various types of cancer, such as the derived NLR (neutrophils/(leucocytes-neutrophils) ratio (dNLR). A high dNLR has been associated with worse survival in several types of cancer. Specifically, it has been linked to lower pathologic complete response (pCR) rates after neoadjuvant chemotherapy (CTx). We investigated the association between systemic inflammation markers (dNLR, LIPI score and platelet-to-lymphocyte ratio [PLR]) and pCR in early TNBC pts treated with CTx + pembrolizumab (Pemb). Methods: Retrospective analysis of pts with early TNBC treated with Pemb + CTx from April 2022 to March 2023. dNLR was estimated from analytical values of peripheral blood collected before treatment (baseline). dNLR was calculated as the ratio of the absolute neutrophil number to the difference between absolute total leukocyte and absolute neutrophil counts. Univariate and multivariate logistic regression analyses were used to explore the association of dNLR with main clinical characteristics and dNLR capability (distributed as a continuous variable, using median cut-off) to predict pCR. Results: The study included 86 TNBC pts with a median age of 51 years (IQR: 42.2 – 56-7). Most pts had stage II disease (64%) and presented grade 3 tumours (n=66; 78.5%). HER2 low tumours represented 27% (n=23) of the cohort. Germline mutations were present in 20 pts (23%) with the following distribution: BRCA1 (n=14), BRCA 2 (n=5) and PALB2 (n=1). The median stromal tumor infiltrating lymphocytes (TILs) was 20% (IQR: 10-30%). The median Ki67 was 70% (IQR:50%-80%). All pts received Pemb. The majority of pts received carboplatin plus paclitaxel, followed by EC90 (n=77 (90%), while 10% (n=9) did not receive anthracyclines. Data concerning surgical outcomes was available in 80 pts. Pathological complete response rate was 61.2% (n=49). Pts achieving pCR presented significantly higher TILs (p< 0.01). Residual cancer burden (RCB) class (n=80) was distributed as follows: 0: 61% (n=49); I: 13% (n=10); II: 20% (n=16); III: 1% (n=1) and non-assigned: 5% (n=4). In pts with germline mutations (n=20), the pCR rate was 85% (n=17). Median dNLR at baseline was 1.30 (interquartile range (IQR): 0.99 – 1.86). High baseline dNLR levels considered a continuous variable was associated with a higher likelihood of achieving a pCR in univariate (OR: 2.59; 95% CI: 1.01–6.6; p-value = 0.046) but not in multivariate (OR: 2.33; 95%; CI: 0.85–6.33; p-value = 0.097) logistic regression analysis (adjusted for stage and histologic grade). High baseline dNLR, defined by the median cut-off, was associated with an increased likelihood of achieving pCR in both univariate (OR: 3.85; 95% CI: 1.47–10.1; p-value = 0.006) and multivariate (OR: 3.72; 95% CI: 1.28–10.8; p-value = 0.016) logistic regression analysis (adjusted for stage and histologic grade). Conclusion: In this real-life cohort of early TNBC pts treated with Pemb and CTx we found similar pCR rates (61.2%) to the ones reported in the KN522 trial. No association between PLR or LIPI score with pCR was evidenced. High baseline dNLR (assessed as a continuous variable or by the median cut-off) was associated with a higher likelihood of pCR in the univariate analysis. In the multivariate analysis, only high baseline dNLR defined by the median cut-off retained an association with pCR after stage and histologic grade adjustment. Despite several limitations, these exploratory data provide initial evidence of a potential association between dNLR values and independent prediction of pCR. Further research to assess the role of dNLR as a predictive marker for pCR in early TNBC pts treated with CTx + immunotherapy is needed. Citation Format: Martina Spotti, Elie Rassy, Alessandro Viansone, Fiona Pham, Layal Rached, Barbara Pistilli, Charles-Antoine Dutertre, Joana Mourato Ribeiro. Impact of systemic inflammation markers in response to neoadjuvant pembrolizumab and chemotherapy in triple-negative breast cancer - a retrospective analysis [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 PO5-13-08.

Abstract PO1-06-12: Phase II study of sitravatinib plus tislelizumab with or without nab-paclitaxel in patients with locally recurrent or metastatic triple negative breast cancer

Abstract Background: The combination of a PD-(L)1 inhibitor plus chemotherapy demonstrated promising anti-tumor activity as first-line therapy for patients (pts) with locally recurrent inoperable or metastatic PD-L1 positive triple-negative breast cancer (TNBC). However, for pts without PD-L1 expression and for those who have failed prior lines of treatment, therapeutic options are still limited. This multi-cohort, phase II trial aimed to evaluate the safety and antitumor activity of 70 mg (cohort A) or 100 mg (cohort B) sitravatinib plus tislelizumab in pts with locally recurrent or metastatic TNBC, and their combination (70 mg sitravatinib plus tislelizumab) with nab-paclitaxel in untreated locally recurrent inoperable or metastatic TNBC pts (cohort C). The efficacy of sitravatinib plus tislelizumab in cohort A and B has been reported with objective response rate (ORR) of 38.1% and 45.0%, respectively. Herein, the preliminary results of cohort C and updated results of cohort A and B were reported. Methods: Pts with untreated locally inoperable or metastatic TNBC were included in cohort C and received 70 mg sitravatinib orally once daily plus 200 mg tislelizumab intravenously on day 1 and 100mg/m2 nab-paclitaxel on days 1 and 8 every three weeks until disease progression or intolerable toxicity. The primary endpoint was ORR. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), duration of response (DOR), 1-year overall survival (OS) rate and safety/tolerability. Based on Simon’s two-stage design, > 9 responders were need in stage 1 (n=18) for the study to continue, and >19 responders were needed by the end of study (n=35) to demonstrate statistical superiority with sitravatinib plus tislelizumab and nab-paclitaxel (assumed to be around 65%) to a historical control of 46% (1-sided alpha of 0.1, power of 80%). Updated analyses were provided for cohort A (Simon’s 2 stage design) and B (Bayesian optimal phase II design). Results: Among the 18 pts in stage 1 of cohort C, 12 of them achieved confirmed response, and therefore the study proceeded to the enrollment in stage 2. As of April 30, 2023, a total of 32 pts were enrolled, with a median age of 51 years. Among the 23 efficacy evaluable pts, unconfirmed ORR was 87.0% (95% CI 66.4-97.2) (including 3 CRs and 17 PRs), with 7 pts not reaching next tumor assessment after reaching CR/PR, and confirmed ORR was 52.2% (95% CI 30.6-73.2). DCR was 95.7%. Any grade of treatment-related adverse events (TRAEs) occurred in 31 (96.9%) pts, and grade ≥3 TRAEs occurred in 5 (15.6%) pts. One (3.1%) patient experienced grade ≥3 immune-related adverse events. SAEs were reported in 3 (9.4%) pts. At the data cut-off date, the median follow-up duration for cohort A and B was 20.4 (range 1.3–24.3) months and 13.3 (range 5.1-19.1) months, respectively. The median PFS in cohort A was 8.2 (95% CI 2.8-12.4) months, and in cohort B was 5.4 (95% CI 4.2-10.9) months. Median OS was not reached in both cohorts. RNA-seq analysis showed that the suppression of immune regulatory pathways and the activation of metabolic pathways promoted early progression. Besides, baseline angiogenesis associated pathway held the potential to predict the favorable response to tislelizumab plus sitravatinib. Conclusion: In the first-line treatment of locally recurrent or metastatic TNBC, preliminary analysis of cohort C showed that sitravatinib combined with tislelizumab and nab-paclitaxel had promising anti-tumor activity with a high ORR, and the combination was generally well tolerated. In TNBC pts with less than three lines of therapy, the chemotherapy-free regimen with sitravatinib plus tislelizumab demonstrated promising PFS after a longer follow-up duration. Citation Format: Lei Fan, Xiyu Liu, Ying Xu, Xinyi Sui, Wenjuan Zhang, Linxiaoxi Ma, Xi Jin, Song-Yang Wu, Han Wang, Yi Xiao, Li Chen, Jiong Wu, Ke-da Yu, Guangyu Liu, Xin Hu, Zhonghua Wang, Yi-Zhou Jiang, Zhi-Ming Shao. Phase II study of sitravatinib plus tislelizumab with or without nab-paclitaxel in patients with locally recurrent or metastatic triple negative 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 PO1-06-12.

Abstract PO5-06-08: Real-world analysis of efficacy, adverse events and predictive biomarkers for advanced triple negative breast cancer (TNBC) treated with immune check point Inhibitors (ICI): A single center experience

Abstract Introduction KEYNOTE-355 investigated the addition of pembrolizumab to chemotherapy in advanced TNBC patients (pts) with PD-L1 positive tumors showing median overall survival (OS) of 23.0 months (mos) and median progression-free survival (PFS) of 16.1 mos. Given significant OS benefit with pembrolizumab, it is the current standard of care while the indication of atezolizumab has been withdrawn due to lack of OS benefit in IMPASSION-130. Clinical efficacy and adverse events in pts on this treatment regimen in clinical practice is unknown and understanding the real-world outcomes of this regimen is critical. Methods We conducted a retrospective, single-center observational study among TNBC pts treated with ICI (Pembrolizumab or Atezolizumab) at Roswell Park Comprehensive Cancer Center from January 2017 to May 2023. Demographics and clinicopathological variables were collected including comorbidities, laboratory data, sites of metastases (mets), treatment received, immune related adverse events (irAEs), and clinical outcomes. Adverse events were reported using the Common Terminology Criteria for Adverse Events v5.0. Serial CT scans were reviewed and response rate was determined using RECIST v1.1. Patient demographic, clinical and outcome characteristics were summarized by treatment and survival outcomes were obtained using standard Kaplan-Meier methods. Associations between survival outcomes and baseline or treatment characteristics were evaluated using Cox regression models using Firth’s method. All analyses were conducted in SAS v9.4 at a significance level of 0.05. Results A total of 44 pts with advanced TNBC treated with ICI were included (23 received pembrolizumab and 21 received Atezolizumab). The study population consisted of all female pts with stage IV disease, median age 53.7 years (IQR 30.4-85.2), 68.2 % (30/44) White, 25.0% (11/44) Black, 34.1% (15/44) obese (BMI≥30). 27.3% (12/44) pts developed any grade irAEs which included myocarditis (4.5%), rash (9.1%), hyperthyroidism (6.8%), hypothyroidism (4.5%), adrenal insufficiency (2.3%), diabetes mellitus (2.4%), colitis (2.3%), and transaminitis (2.3%). Distribution of reported irAE was 25% grade 1 (3/12), 66.7% grade 2 (8/12) and 8.3% grade 3 (1/12). 75% pts (33/44) received standard treatment (ICI+ chemotherapy) of which 72.7 % (24/33) received it in the first-line setting. Median OS in pts treated in first line was 16.2 mos (95% CI, 10.7-NR) and median PFS was 4.4 mos (95% CI, 2.7-8.4). Overall response rate (ORR) was 29.1% (7/24) of which 8.3% (2/24) had complete response and 20.8% (5/24) had partial response. ORR was 22.2 % (2/9) in pembrolizumab cohort and 33.3 % (5/15) in atezolizumab cohort. Among pts with first line treatment, obese pts were found to have improved PFS compared to non-obese (11.5 vs 3.8 mos, univariate hazard ratio (HR) 0.46, 95% CI 0.23-0.93, p= 0.031), and this difference was maintained in multivariable analysis even after adjusting for age (adjusted HR (aHR) 0.40, 95% CI 0.17-0.98, p= 0.044). Pts with brain mets had poor extracranial PFS compared to those without brain mets (2.8 vs. 5.2 mos, HR 2.25, 95% CI 1.08-4.68, p= 0.036), however this difference was not observed when further adjusted for age (aHR 2.27, 95% CI= 0.91-5.68, p= 0.08). Conclusion Clinical outcomes in our study were inferior to KEYNOTE-355 where median PFS was 16.1 mos and OS was 23.0 mos and ORR was 52.7% for PD-L1 positive population. This may reflect a more heterogeneous population of pts treated in routine clinical practice who are typically less fit than pts on clinical trials. Our study found improved outcomes among obese patients, similar to data reported in other disease settings. These data warrant multi-center validation with larger number of patients. Citation Format: Archit Patel, Arya Mariam Roy, Malak Alharbi, Kristopher Attwood, Chi-Chen Hong, Song Yao, Thaer Khoury, Amy Early, Tracey O'Connor, Ellis Levine, Shipra Gandhi. Real-world analysis of efficacy, adverse events and predictive biomarkers for advanced triple negative breast cancer (TNBC) treated with immune check point Inhibitors (ICI): A single center experience [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 PO5-06-08.

Abstract RF02-07: Precocious modulation of metabolic and immunological parameters predicts tumor response to fasting-mimicking diet plus chemotherapy in patients with early stage TNBC

Abstract Background: Preclinical studies showed that severely calorie restricted fasting-mimicking diets (FMDs) enhance the antitumor efficacy of chemotherapy (CT) or immunotherapy (IO) in murine triple negative breast cancer (TNBC) models. These effects are mediated by a combination of blood glucose reduction and positive immunomodulatory effects. Moreover, combining fasting and metformin produced synergistic anticancer effects in a broad range of tumor models. The BREAKFAST trial was designed to investigate if FMD, plus/minus metformin, could increase the antitumor activity of neoadjuvant CT in patients with stage I-III TNBC. Methods: BREAKFAST (NCT04248998) is a randomized, non-comparative, phase II, pilot trial that enrolled stage I-III (cT>1 cm) TNBC patients (pts) candidate to receive 4 cycles of neoadjuvant CT with doxorubicin-cyclophosphamide every 3 weeks, followed by 12 cycles of weekly paclitaxel. Pts were randomized 1:1 to receive: CT plus 5-day FMD every 3 weeks, up to 8 cycles (arm A); CT plus FMD plus daily metformin (1700 mg) (arm B). The primary study endpoint was the rate of pCR in either experimental arm. Secondary/exploratory endpoints included safety, compliance, and biomarker analyses based on blood metabolomics and tumor transcriptomics analyses at different timepoints. Results: Between June 2020 and February 2022 we enrolled 30 pts. Then, the study was interrupted after the introduction of chemo-immunotherapy (CT-IO) as a standard neoadjuvant therapy for early stage TNBC pts. Among 30 pts, 13 were treated with CT plus FMD, while 17 pts received CT plus FMD plus metformin. Overall, pCR rate was 56.6%, i.e., significantly higher than pCR rates reported with anthracycline-taxane CT alone in previous phase II/III trials (26-39%), with no significant differences among treatment arms (p=0.49). The FMD acutely reduced blood glucose, insulin and LDH levels, which reflects a reduction in systemic and/or tumor glucose metabolism. Of note, precocious LDH reduction was more pronounced in patients undergoing pCR. RNA-seq analysis of tumor samples revealed a significant downmodulation of glycolysis and TCA cycle pathways after one treatment cycle, paralleled by an increase of intratumor activated T cells, memory T cells and NK cells, as estimated by deconvolution analyses of tumor transcriptomic data. Of note, these changes were observed only in patients achieving pCR. While intratumor metabolic changes were similar in the two treatment arms, the modulation of intratumor immunity was more pronounced in patients not receiving metformin. Conclusion: Preoperative CT plus cyclic FMD (plus/minus metformin) results in excellent pCR rates in localized TNBC patients. Early on-treatment downregulation of systemic and intratumor metabolic parameters related to glucose metabolism predicts pCR, and this is independent of metformin use. Based on results of this study, we recently initiated a large, multicentric trial, namely the BREAKFAST-2 (NCT05763992) study, which will investigate if adding cyclic FMD to neoadjuvant CT-IO increases pCR rates in ~ 145 pts with stage II-III TNBC. Citation Format: Francesca Ligorio, Giovanni Fucà, Andrea Vingiani, Fabio Iannelli, Riccardo Lobefaro, Leonardo Provenzano, Lucrezia Zanenga, Cristina Ferraris, Antonino Belfiore, Silvia Brich, Alessia Bertolotti, Gianfranco Scaperrotta, Catherine Depretto, Antonia Martinetti, Elisa Sottotetti, Paola Antonia Corsetto, Giulia Valeria Bianchi, Giuseppe Capri, Secondo Folli, Saverio Minucci, Marco Foiani, Massimiliano Pagani, Giancarlo Pruneri, Filippo De Braud, Claudio Vernieri. Precocious modulation of metabolic and immunological parameters predicts tumor response to fasting-mimicking diet plus chemotherapy in patients with early stage TNBC [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 RF02-07.

Abstract 1173: T cell receptor diversity in buffy coat samples from subsets of breast and ovarian cancer patients

Abstract Background: Immunotherapy, mainly by the use of immune checkpoint inhibitors (ICI), has been established as a standard option for both, solid tumors and hematological malignancies. Unfortunately, this success has only been replicated in a subset of patients (pts) with gynecological cancers. In ovarian cancer (OC), response rates to ICI monotherapy were low and in breast cancer (BC), only the subgroup of triple-negative BC (TNBC) pts showed an improved outcome by the addition of ICI. One reason for limited success of immunotherapy might be an impaired immune system. In this regard, monitoring the T cell receptor (TCR) repertoire could provide key insights into adaptive immune responses to ultimately understand disease initiation, progression and treatment response. Here we elucidated TCR alpha, beta, gamma and delta in buffy coats of pts with non-metastatic OC as well as non-metastatic and metastatic TNBC and compared the results with healthy donors (HDs). Methods: RNA was isolated from buffy coat samples of 20 HDs, 10 treatment-naïve primary OC pts, 14 treatment-naïve, non-metastatic TNBC pts (participating in the phase II neomono trial) and 19 pts with metastatic TNBC by a modified QIAamp RNA Blood Mini protocol. A survey of the TCR diversity and mapping of common and unique TCRs was done using the QIAseq Targeted RNA Panel Human TCR panel for all known T-cell receptors (alpha, beta, gamma, delta). Results: Regardless of the cancer entity, a significant reduction in TCR diversity was observed compared to HDs with the greatest differences observed in the delta receptors. When OC samples were compared with HDs, the difference in diversity was highly significant for all TCR subtypes (TCRalpha: p=0.013; TCRbeta: p=0.008; TCRgamma: 0.008; TCRdelta: 0.006). Similar results were obtained for non-metastatic TNBC (TCRalpha: p=0.0002; TCRbeta: p=0.0001; TCRgamma: p=0.002; TCRdelta: p=0.002) as well as metastatic TNBC patients (TCRalpha: p=0.001; TCRbeta: p=0.001; TCRgamma: p=0.005; TCRdelta: p=0.003) when their TCR diversity was compared to HDs. Interestingly, no significant differences in diversity were obtained when treatment-naïve non-metastatic TNBC pts were compared with heavily pretreated metastatic TNBC pts. The lowest diversity was found in BC pts compared to the OC pts. Conclusion: We have initiated a survey of the TCR diversity in TNBC and OC patients. Further evaluations will include the correlation of these findings with clinical characteristics and outcome. Whether the reduced TCR diversity represents T cell exhaustion or T cell specialization cannot yet be deduced from the results. Nevertheless, the addition of a TCR diversity score could provide an additional metric which may help provide patient guidance when integrated into a multi-modal molecular test. Citation Format: Corinna Keup, Cornelia Kolberg-Liedtke, Song Tian, Samuel J. Rulli, Siegfried Hauch, Paul Buderath, Oliver Hoffmann, Rainer Kimmig, Sabine Kasimir-Bauer. T cell receptor diversity in buffy coat samples from subsets of breast and ovarian cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1173.

Pathologic complete response (pCR) to neoadjuvant treatment (NAT) with carboplatin, nab-paclitaxel and anthracycline in early and locally advanced triple-negative breast cancer (TNBC).

e12608 Background: Achieving a pCR (absence of residual invasive disease in breast and measurable disease in any of the axillary nodes sampled, ypT0/is and ypN0) after NAT correlates with improved survival. TNBC phenotype have a poor prognosis. However, it is associated with higher NAT response rates. With traditional schemes based on anthracyclines and taxanes, pCR rates of around 25-40% are obtained. Different schemes have been studied providing an increase in pCR such as using nab-paclitaxel, platinum salts, bevacizumab or dose dense (dd) anthracyclines. The purpose of the present study is to explore feasibility, toxicity and pCR of new aproach with carboplatine, nab-paclitaxel and antracycline in TNBC. Methods: Retrospective study with early and locally advanced TNBC pts, ECOG 0-1, without contraindications to antracyclines, were included. Treatment consisted of carboplatine AUC2 with nab-paclitaxel 80 mg/m2 i.v. weekly for 12 doses followed by epirubicin 90 mg/m2 (elderly pts recieved at 75 mg/m2) with cyclophosphamide 600 mg/m2 i.v., every 2 weeks (dd) or 3 weeks (if pts had G3-4 toxicity) for 4 doses. G-CSF support was allowed in pts with neutropenia G3-4. Pts with residual disease after NAT were offered capecitabine as adjuvant treatment. The primary endpoint was pCR. Results: From 02/2018 to 06/2022, 96 pts was included. Median age was 53 years (27-78). Clinical stage was I in 16 pts, II in 50 pts and III in 30 pts (N+ in 40'6%). 98% pts had tumours with a Ki67 20% or higher. 36’5% pts was premenopausal. 10 pts were germline BRCA mutated (8/10 gBRCA1, 2/10 gBRCA2) 50/96 pts (55’2%) had dd epirubicin-cyclophospamide (EC) and 44’8% pts recieved EC every 3 weeks (for G3 adverse events (AE)). pCR in pts who had dd treatment was 65’4% and 40’9% in pts with EC non-dd (p 0’016). 89’9% pts with residual disease completed adjuvant treatment with 8 cycles of capecitabine. 53/96 pts had an AE related with NAT. Neutropenia G3-4 (45’5% pts, all of them recieved dd treatment) and any grade of alopecia and mucositis (60% and 25% respectively) were the most frecuent AE reported. Pts with neutropenia G3-4 on blood test recieved G-CSF in subsequent cycles with resolution of haematological AE. All pts with dd treatment recieved G-CSF. One patient had a disease progression by radiological evaluation during the treatment. During follow-up 9 pts relapsed (1 had a pCR with NAT) and 5 pts died for progression disease. Conclusions: NAT on TNBC pts with carboplatine, nab-paclitaxel and antracycline dd is a feasible, safe and highly effective option. Even though survival analysis is not yet mature in our study, pCR has been shown to be a surrogate for overall survival. The excellent results obtained with this scheme, make it a good treatment option and could be an alternative to pembrolizumab (Keynote-522) in pts with autoinmmune diseases or immune-AE due to similar pCR.

Abstract 1940: Outcomes of patients treated with neoadjuvant chemotherapy for breast cancer at a safety net hospital

Abstract Background: Neoadjuvant chemotherapy (NAC) is administered before surgery and expected to benefit certain breast cancer (BC) patients (pts). This study inspected outcomes of triple negative BC (TNBC), hormone receptor (HR) positive (+) HER2 negative (-), and HER2+ BC pts treated with NAC at John Peter Smith Hospital (JPS) in Tarrant County, TX. Methods: It is an IRB exempted retrospective review of JPS Oncology and Infusion Center’s registry data. Eligible pts were diagnosed with TNBC, HR+ HER2-, or HER2+ BC from 1/1/2016 to 12/31/2019 and underwent NAC. Age, race, NAC regimen, tumor grade, recurrence, and pt survival were collected from EPIC EMR. NCCN guidelines were used to standardize clinical prognostic and pathologic anatomic stages. Decrease in stage by at least one level was considered as improvement. Results: Refer to table for additional results. Total of 104 pts. 22 (21.2%) had recurrence, 14 (14.5%) had died. Using the full cox proportional hazard model, TNBC pts had a 3.214 times higher hazard of death/recurrence compared to other subsets (95% CI: 1.261, 8.193; p= 0.0145). 70 (67.3%) pts showed improvement in stage. 34 (32.7%) achieved pathological complete response (pCR). When compared to pts with residual disease, achieving pCR reduced hazard of death/recurrence by 71.6% (HR: 0.284; 95% CI: 0.095, 0.849; p= 0.0243). Conclusion: A clear unmet need is poor survival of Black TNBC pts. Safety net hospitals, like JPS, disproportionately treat Black pts. We show that attaining pCR correlates with improved survival, but less than a quarter of TNBC pts attained pCR. New NAC regimens with Pembrolizumab has become standard of care for TNBC pts since 2021 due to higher pCR rates. Still, there is a need for better NAC regimens to improve pCR in TNBC overall and clinical trials on new regimens should include Black pts. Also, more than a third of HR+ HER2- pts upstaged in LN after NAC. This suggests a need for pre-NAC radiology staging methods and better NAC regimen testing for this subset. TNBC(32 patients) HR+, HER2-(29 patients) HER2+(43 patients) TOTAL(104 patients, 103 women) Median Age Median Age 58 50 53 53 Racial Distribution of Patients Non-Hispanic White 9(28.1%) 11(37.9%) 11(25.6%) 31(29.8%) Black 18(56.3%) 12(41.4%) 15(34.9%) 45(43.3%) Hispanic 4(12.5%) 2(6.9%) 10(23.3%) 16(15.4%) Asian 1(3.1%) 4(13.8%) 7(16.3%) 12(11.5%) Clinical Prognostic Stage Before NAC and Surgery 1 1(3.1%) 0(0%) 9(20.9%) 10(9.6%) 2 8(25%) 13(44.8%) 20(46.5%) 30(28.8%) 3 22(68.8%) 16(55.2%) 14(32.6%) 52(50%) 4 1(3.1%) 0(0%) 0(0%) 1(0.9%) Pathologic Anatomic Stage After NAC and Surgery pCR 7(21.9%) 3(10.3%) 24(55.8%) 34(32.7%) 1 8(25%) 3(10.3%) 14(32.6%) 24(23.1%) 2 9(28.1%) 9(31%) 3(7%) 21(20.2%) 3 8(25%) 14(48.3%) 2(4.7%) 24(23.1%) 4 0(0%) 0(0%) 0(0%) 0(0%) Tumor Stage Difference Before/After Surgery Improvement 24(75%) 11(37.9%) 35(81.4%) 70(67.3%) Deterioration 1(3.1%) 7(24.1%) 0(0%) 8(7.7%) No Change 7(21.9%) 11(37.9%) 8(18.6%) 26(25%) Recurrence Recurrence 10(31.3%) 4(13.8%) 8(18.6%) 22(21.2%) Patients survived as of 9/19/2022 Survival 25(78.1%) 27(93.1%) 38(88.4%) 90(86.5%) Additional Significant Results Completion of NAC regimen 89 (85.6%) total pts Lymph Node (LN) Upstaging for HR+ HER2- 6 (20.7%) pts showed improvement in LN while 11 (37.9%) upstaged in LN pCR in Black TNBC pts Only 16% of Black pts achieved pCR Citation Format: Prakriti Srivastava, James-Michael Blackwell, Jolonda Bullock, Riyaz Basha, Kalyani Narra. Outcomes of patients treated with neoadjuvant chemotherapy for breast cancer at a safety net hospital [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1940.

Abstract P2-13-05: Triple Negative Breast Cancer (TNBC) patients are more likely to digitally explore clinical trial options and prior to receiving treatment for advanced disease compared to non-TNBC patients

Abstract Introduction: Triple-negative breast cancer (TNBC), an aggressive form of breast cancer (BC) that is associated with poor prognosis, accounts for 10-15% of all BCs. Chemotherapy remains the standard of care (SOC) for advanced disease, with limited clinical benefit. Oncology clinical trials (CTs) are globally recommended and encouraged as the preferred treatment (tx) option for any cancer patient (pt). ‘TrialJectory’ (TJ) is an artificial intelligence (AI)-based technology that matches pts to oncology CTs. Here, we identified distinct characteristics of TNBC pts who signed up to the TJ platform compared to non-TNBC pts. Methods: Using AI and an unsupervised natural language processing approach, the TJ platform clinically matches pts to CTs. Matching is achieved by pt response to an online dynamic questionnaire (www.trialjectory.com) that collects detailed clinical data including clinico-pathologic characteristics, tx history, general health, and comorbidities. Those are compared to the eligibility criteria of available CTs to yield a high-quality actionable matched-trial list. Results: Between 1/2020 and 12/2021, out of 9796 BC pts that signed up, 2688 were TNBC pts (27%). There was no significant difference in age at sign-up between TNBC and non-TNBC patients (median age of 57 years vs 58 years, respectively). Consistently with Non-hispanic black (NHB) race prevalence in the different molecular subtypes in the general US population, NHB race had higher signup rate in TNBC compared to non-TNBC (9.95% vs 5.76%, respectively). TNBC pts signed up at a later disease stage compared to non-TNBC pts (19% of TNBC reported having a stage 1 disease compared to 27% of non-TNBC pts, p< 0.001).A significantly higher percentage of pts with advanced/metastatic TNBC signed up to the TJ platform before starting tx compared to non-TNBC patients (34% vs 22%, respectively, p< 0.001). Furthermore, there was a significant difference in the willingness to travel any distance within the US for a matched clinical trial between TNBC and non-TNBC pts (39% vs 34%, respectively, p< 0.001). Conclusions: In this study, we found significant differences in the characteristics of TNBC vs non-TNBC pts that have signed up to the TJ platform. There was an up to 2-fold enrichment of TNBC on the TJ platform pts compared to their frequency in the general population. While previous studies do not show a difference in stage distribution between different subtypes, TNBC patients initiated their search for CTs at a higher stage. In addition, advanced TNBC patients started their search earlier in their journey, before starting chemotherapy. This may reflect the lack of effective SOC and possibly, the motivation to avoid the use of chemotherapy. This is also supported by the willingness of TNBC patients to travel farther in order to identify and enroll in a CT compared to non-TNBC pts. Importantly, the motivation of TNBC pts to travel any distance has not been reduced despite the COVID-19 pandemic, reflecting a strong drive of this pt population to enroll in CTs. It also demonstrates that with the right access, diverse patient populations are willing to participate in clinical trials. In sum, TNBC pts are more likely to explore CT options, in the advanced stage setting, earlier in their journey. This study demonstrates the power of TJ platform for clinico-pathologic characterization and diverse pt groups, including their drivers and behavioral choices during their battle with cancer. Citation Format: Michal Safran, Yelena Lapidot, Tzvia Bader, Avital Gaziel. Triple Negative Breast Cancer (TNBC) patients are more likely to digitally explore clinical trial options and prior to receiving treatment for advanced disease compared to non-TNBC patients [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-13-05.

Abstract P4-07-40: Magnetic resonance imaging (MRI) and clinicopathological analysis of triple-negative breast cancer (TNBC) patients (pts) treated with primary anthracyclines(A)/taxanes(TX)-based chemotherapy

Abstract Background Radiological complete response (CR-MRI) to neoadjuvant chemotherapy (NAC) by MRI predicts pathologic complete response (pCR) rates in pts with TNBC treated preoperatively with A/TX-based regimens and in some studies, it correlates with disease-free survival (DFS). The main aim of this study was to assess the relevance of the MRI response to primary chemotherapy associated with clinical stage and HER2 expression (Zero vs Low), in a cohort of 143 TNBC pts treated with A and TX +/- carboplatin (CP) in the NAC setting. Methods Retrospective study of pts treated with NAC for TNBC between January 2002 and June 2021, who underwent MRI to assess tumour response before NAC, after 4 cycles of anthracycline and cyclophosphamide (AC) and after TX. Survival analysis was based on the Kaplan-Meier and survival curves were compared using the log-rank test. A p value of less than 0.05 was considered as statistically significant. Results A total of 143 TNBC pts with a median age of 52 years; 7, 63 and 73 pts had stage I, II and III disease, respectively. The NAC regimen consisted in 117 pts 4 cycles of AC followed by TX and in 24 pts the same adding CP (in 21 pts with non-CR-MRI, 2 with CR-MRI and 1 without MRI after AC). PCR was observed in 41%. Of 30 pts with CR-MRI after AC, 83% obtain a pCR (p< 0.001), and of 52 pts with CR-MRI at the end of NAC, 70.7% obtain a pCR (p< 0,001) of which 90% had a CR-MRI after AC. Adding CP increased pCR by 6% (p=0.564). According HER2-zero vs low expression, the pCR was 38% and 47% respectively, with no significant differences. With a median follow-up of 60 months, 34% recurred and 16% died of TNBC. In pts with pCR, the DFS at 5 years (y) was 96% and 47% for pts without pCR (p< 0.001), with a DFS of 91% if CR-MRI at the end of NAC and 48% if non-CR-MRI (p< 0.001). In HER2-Zero tumours the DFS at 5 y was 64% vs 66% in HER-2 low. Interestingly, overall survival (OS) at 5 y was 72% in HER2-Zero and 84% in HER2-low (p=0.080). Conclusions Performing serial MRI in the course of NAC in TNBC may be a reliable indicator of pCR, adding platinum to TX in pts with CR-MRI may increase pCR rate. HER2-Zero expression in TNBC, seems to confer worse OS rates. Citation Format: Marina Sierra Boada, Luis Antonio Fernandez, Elsa Dalmau, Gemma Llort, Maria Marin, Pablo Andreu, Natalia Lopez, Carla Climent, Marta Rodriguez, Sandra Soriano, Miquel Angel Segui. Magnetic resonance imaging (MRI) and clinicopathological analysis of triple-negative breast cancer (TNBC) patients (pts) treated with primary anthracyclines(A)/taxanes(TX)-based chemotherapy. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-07-40.

Abstract P4-07-45: Treatment strategies for advanced triple negative breast cancer patients as per routine clinical practice: analysis from the observational study GEICAM/2014-03 (RegistEM)

Abstract Background: Triple negative breast cancer (TNBC) is well known for its more aggressive course and poorer prognosis compared to other BC subtypes. RegistEM study provides real world data to understand the distribution of BC subtypes in the advanced setting, being its primary objective. Biological samples collection is part of its procedures. This is a non-interventional cohort study and 1,907 patients (pts) have been enrolled up to now (females and males) with advanced BC (ABC), diagnosed from Jan-2016 to Dec-2019, either after recurrence or as first BC diagnosis, in 38 Spanish sites. These pts will be followed for at least 5 years. Methods: In the current analysis (cut-off date 08/April/2022, database ongoing), we describe characteristics, treatment patterns and outcomes, including comparison between recurrent and de novo disease, of 157 pts with advanced TNBC included in the RegistEM study. Those pts represent the 10% of pts available in the database at the cut-off date and with ABC diagnosis up to December 2018 (n=1559). The BC clinical subtypes were histologically confirmed on the most recent tumor lesion (metastatic [M] or primary BC) before starting with the 1st-line therapy. Results: At first ABC diagnosis, 73% pts had recurrent early BC (EBC), 26% de novo MBC and 1% unresectable locally ABC (ULABC). Median age was 57 years (range 30-88), all pts were women, 98% Caucasian and 65% postmenopausal. Family history of BC and/or ovarian cancer was reported in 37% pts, and a hereditary-risk genetic test was performed in 59 of 147 pts. Germline BRCA1/2 and TP53 were the most frequently mutated genes, 21% (6/28) and 47% (8/17) pts, respectively. Visceral involvement was present in 69% pts (similar between recurrent EBC and de novo ABC, although brain metastases were only present in the recurrent EBC group), and ≤ 2 metastatic locations in 59%. In 61% (70/115) pts with recurrent EBC, the subtype was assessed in metastatic lesions, and 39 pts of them also had TN subtype in primary BC. In terms of the most frequent therapies by line: 1) 1st-line: chemotherapy (CT) (60%) and CT/biological therapy (BT) (39%). Of the 87 pts with CT alone, monotherapy was the preferred option in 57% pts (capecitabine 25%, taxanes 16%, and eribulin or vinorelbine, 5% each). Bevacizumab was the most frequent BT (79%) combined with CT (single agent in 56% pts, mostly taxanes and capecitabine). Progressive disease (PD) was reported in 85% pts (similar in pts with both recurrent and de novo MBC or ULABC); 2) 2nd-line: CT (79%) (monotherapy capecitabine, eribulin, taxanes) and CT/BT (17%) (CT-containing bevacizumab 82%). Progression was reported in 92% pts; 3) 3rd-line: CT (90%) (eribulin 33%, platinum-based 25%) and CT/BT (9%) (CT-containing bevacizumab 67%). Progression was reported in 88% pts. At database cut-off date, death was reported in 133 (85%) pts, mainly because of PD. Overall survival (OS) was similar between both groups, recurrent and de novo MBC. Conclusion: In this population of Spanish TNBC pts with ABC, three quarters had recurrent disease. De novo ABC pts had a higher proportion of non-visceral metastases, with absence of brain involvement at the first diagnosis. Single-agent CT and CT plus bevacizumab were the most frequent therapies, and OS was similar between recurrent and de novo MBC pts, although numerically higher in the later group. Citation Format: Silvia Antolin Novoa, César A Rodríguez, Josefina Cruz, Sara López-Tarruella, Ariadna Tibau, Encarna Adrover, Ana Miguel, Mireia Margelí, Purificación Martínez, María Hernández, Antonio Antón, Álvaro Rodríguez-Lescure, Catalina Falo, Isabel Álvarez, Diego Malón, Raquel Andrés, José L Alonso-Romero, César Gómez, J. José Illaramendi, Ruth Campo, Juan José Miralles, Susana Bezares, Federico Rojo, Angel Guerrero-Zotano. Treatment strategies for advanced triple negative breast cancer patients as per routine clinical practice: analysis from the observational study GEICAM/2014-03 (RegistEM) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-07-45.

Abstract PD9-05: Stromal tumor-infiltrating lymphocytes identify early-stage triple-negative breast cancer patients with favorable outcomes at 10-year follow-up in the absence of systemic therapy: a pooled analysis of 1835 patients

Abstract Background: The prognostic value of stromal tumor-infiltrating lymphocytes (TILs) as a biomarker for triple-negative breast cancer (TNBC) has been extensively demonstrated in patients (pts) receiving (neo)adjuvant systemic therapy. In addition, several small studies suggest that a subset of pts with early-stage TNBC and high TILs have excellent long-term outcomes, even in the absence of systemic therapy [1-3]. However, data on the absolute risk of TNBC recurrence according to TIL levels in the absence of systemic therapy are limited and critical to inform the design of future systemic therapy de-escalation clinical trials. Methods: We conducted an individual patient data pooled analysis of 12 international cohorts of pts with TNBC treated with locoregional therapy but no systemic therapy. TNBC was defined as tumors with estrogen and progesterone receptor of < 1% and HER2 negative (IHC 0, 1+ or IHC 2+ and FISH negative) per local evaluation. TILs were locally assessed in hematoxylin & eosin-stained slides according to the International Immuno-Oncology Biomarker Working Group guidelines (www.tilsinbreastcancer.org). We used the Kaplan-Meier method to assess survival outcomes according to prespecified TIL thresholds: 30% and 50%. Confidence intervals (CI) for survival probabilities were calculated using a percentile bootstrap method. The primary endpoint was invasive disease-free survival (iDFS, STEEP 2.0 definition). Key secondary outcomes included recurrence-free survival (RFS), distant disease-free survival (DDFS) and overall survival (OS). Results: 1,835 pts diagnosed with TNBC between 1982 and 2017 who did not receive systemic therapy were included. The median age at diagnosis was 56 (IQR 38-71). Menopausal status was known in 1,184 women, of whom 78% were post-menopausal. The median tumor size was 2.0 cm (IQR 1.2-2.6). Most pts (87%) had no axillary lymph node involvement (N0). Most tumors were invasive ductal carcinoma (74%) and grade 3 (70%). The median level of TILs was 15% (IQR 5-40). The median duration of follow-up was 30.4 years (95% CI 29.9, 31.1). A total of 950 (52%) iDFS, 828 (45%) RFS, 767 (42%) DDFS events, and 604 (33%) deaths were observed. In multivariable analyses, higher TILs were independently associated with improved iDFS, RFS, DDFS, and OS beyond clinicopathological factors (likelihood ratio p< 10e-6). Each 10% increment in stromal TILs was associated with an 8% (95% CI: 6-11), 10% (95% CI: 7-13), and 13% (95% CI: 10-15) reduction in the risk of experiencing an iDFS, RFS or DDFS event, and with a 12% (95% CI: 9-15) reduction in the risk of death. iDFS, RFS, DDFS and OS rates according to different TIL thresholds and nodal status are shown in the Table. Of note, the RFS estimates (which exclude second non-breast primaries and contralateral breast cancers) were consistently higher than the iDFS counterparts (which include both), consistent with a high rate of contralateral breast cancers and second primary tumors in this cohort. Notably, patients with node-negative—and especially stage I—TNBC with high TILs had excellent survival rates at 10-year follow-up. Conclusion: TILs are highly prognostic in pts with systemically untreated early-stage TNBC. Pts with pN0 (and especially stage I) TNBC with high TILs exhibited very favorable long-term outcomes even in the absence of systemic therapy. These data define the natural history of TIL-rich TNBC pts and are crucial to identifying the optimal patient population for future chemotherapy and immunotherapy de-escalation clinical trials.

74P The safety, tolerability, and preliminary antitumor activity of sitravatinib plus tislelizumab in patients (pts) with locally recurrent or metastatic triple-negative breast cancer (TNBC): A multi-cohort, phase II trial

This is a multi-cohort, phase II trial to evaluate the safety and preliminary antitumor activity of 70 mg (cohort A) or 100 mg (cohort B) sitravatinib QD plus tislelizumab in pts with locally recurrent or metastatic TNBC, and their combination with nab-paclitaxel in untreated locally recurrent inoperable or metastatic TNBC pts (cohort C). The preliminary result of cohort A has been reported with ORR of 38.1% (Lei Fan. JCO 2022 40:16_suppl). This analysis aims to report the updated analysis in cohort A and the interim results in cohort B.

Abstract 2796: ctDNA prognosis in adjuvant triple-negative breast cancer

Abstract Background: Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype, even in early stages. Evidence of molecular residual disease (MRD), after treatment with curative intent (surgery, chemotherapy), predating macroscopic recurrence can provide rationale for early therapeutic intervention, potentially improving patient outcomes. Longitudinal evaluation of circulating tumor DNA (ctDNA) is emerging as a promising early marker of treatment efficacy and recurrence, validated to pre-date recurrence by radiological imaging. However, data in early TNBC (eTNBC) are limited. Here we investigate the prognostic value of longitudinal ctDNA monitoring in eTNBC patients post-surgery and after adjuvant chemotherapy (ACT) using a custom bespoke ctDNA assay. Methods: Tumor tissue and longitudinal post-surgical plasma samples were collected and analyzed from 186 patients enrolled in the phase 3 BEATRICE clinical study (NCT00528567). Samples from each patient were whole exome sequenced to identify up to 16 SNVs for ctDNA monitoring. ctDNA status was measured longitudinally and correlated with baseline prognostic factors as well as invasive disease free survival (iDFS) and overall survival (OS). Results: Baseline ctDNA (b-ctDNA), evaluated post-surgery and prior to chemotherapy was detected in 19.9% (36/181) of patients. b-ctDNA was positively associated with large tumors and lymph node (LN) involvement, and negatively correlated with presence of stromal tumor infiltrating lymphocytes (TILs). b-ctDNA presence was a stronger predictor of shorter IDFS and OS compared to LN involvement (HR IDFS: 4.36 [2.47-7.7] vs 1.86 [1.08-3.19]; HR OS: 4.01 [1.6-10.07] vs 2.89 [1.39-6]]), respectively). Remarkably, b-ctDNA prognostic value was restricted to LN+ pts (HR IDFS: 10.94 [3.2-37.41]) vs LN- pts (HR IDFS 1.61 [0.49-5.36]). ctDNA positivity after ACT was observed in 21.5% (40/186) of patients and was associated with reduced IDFS and OS (HR: 8.36 [4.62-15.1] and 18.45 [6.79-50.17]), independent of LN involvement. Upon chemotherapy treatment, the median time to first ctDNA positivity occurrence was 13 months (range 3-42.3 mo) and the median lead time from ctDNA detection to radiographic recurrence was 6.1 months (range 0-30.5 mo). Akaike information criterion (AIC, p<0.05) indicated that ctDNA detected post-surgery or post-chemotherapy identifies patients at the highest risk of disease progression even after adjustment for LN and TILs status as well as the tumor size. Conclusions: ctDNA, both at post-surgery and post-ACT, provides additional prognostic value beyond the known risk factors of LN involvement, tumor size and TILs. Post-op ctDNA+ provides an independent and stronger indicator of poor prognosis than any other evaluated baseline covariates. Our data show that TNBC pts that are ctDNA+ post-surgery are at the highest risk of recurrence and death and are underserved by current SOC treatment. Citation Format: Luciana Molinero, Derrick Renner, Hsin-Ta Wu, Nina Qi, Rajesh Patel, Ching-Wei Chang, Himanshu Sethi, Alexey Aleshin, Carlos Bais, David Cameron. ctDNA prognosis in adjuvant triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2796.