Advanced Triple-negative Breast Cancer Patients Research Articles

Efficacy and safety of Anlotinib based neoadjuvant chemotherapy for locally advanced triple negative breast cancer (TNBC)

BackgroundAnlotinib, an oral multitarget tyrosine kinase inhibitor, has shown the ability to inhibit tumor angiogenesis. This study aimed to assess the effectiveness and safety of anlotinib plus docetaxel, epirubicin, and cyclophosphamide (TEC) as a neoadjuvant chemotherapy regimen for locally advanced TNBC.MethodsLocally advanced TNBC patients who had received no prior systemic treatment were eligible for this study. The enrolled patients were scheduled to undergo six cycles of anlotinib (12 mg, d1-14, q3w) plus docetaxel (75 mg/m2, d1, q3w), epirubicin (75 mg/m2, d1, q3w) and cyclophosphamide (600 mg/m2, d1, q3w) prior to surgery, unless there was disease progression or severe toxicity. The primary objective of this study was the safety of this therapeutic regimen, and the secondary objective was the tumor response. The safety of this regimen was assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 and the efficacy of this treatment was measured using the Response Evaluation Criteria in Solid Tumors version 1.1.ResultsA total of 18 patients were included in this study. Participants completed an average of 5.56 neoadjuvant treatment cycles. The objective response rate (ORR) was 83.33%, and the disease control rate was 100%, respectively. The pCR was 55.6%. No patients discontinued therapy because of Adverse effects (AEs). Grade 3 or 4 AEs were observed in 5 cases (27.8%), with neutropenia and palmar-plantar erythrodysesthesia syndrome being the most common.ConclusionsAnlotinib combined with TEC as neoadjuvant therapy demonstrated manageable toxicity and promising antitumor activity for locally advanced TNBC. Further investigation of this combination regimen is warranted.

Efficacy and safety of PARPis combined with an ICIs for advanced or metastatic triple-negative breast cancer: a single-arm meta-analysis.

Although the intervention for triple-negative breast cancer (TNBC) patients has improved and survival time has increased, the combination of immune checkpoint inhibitors(ICIs) and PARP inhibitors (Poly ADP-Ribose Polymerase inhibitors, PARPis) is still controversial. Previous studies revealed that the combined use of ICIs and PARPis led to increased antitumor activity. However, most of these combined regimens are nonrandomized controlled trials with small sample sizes. The purpose of this meta-analysis was to evaluate the efficacy and safety of ICIs combined with PARPis in patients with advanced or metastatic TNBC. The PubMed, Embase, Cochrane Library and Web of Science databases were systematically searched. The results including the objective remission rate (ORR), disease control rate (DCR), progression-free survival (PFS) and adverse events (AEs), were subjected to further analysis. Four studies involving 110 subjects were included in this meta-analysis. The combined ORR and DCR were 23.6% and 53.6%, respectively; while the ORR and DCR of BRCAmut patients were 38.1% and 71.4%, respectively. The median PFS of the patients was 4.29 months. As for safety, the most common AEs were nausea (49.0%), anemia (44.3%) and fatigue (40.6%). Most of them were grade 1 or 2, and the incidence of adverse events ≥ III was obviously low. Except for anemia, the incidence of AEs ≥ III was < 10%. This meta-analysis revealed that the combination of ICIs and PARPis has good efficacy and safety for advanced or metastatic TNBC patients.

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 PO1-15-08: Genomic characterization of triple-negative breast cancer metastases reveals PKD1 as a novel biomarker for immunotherapy

Abstract Background: While primary triple-negative breast cancer (TNBC) garners significant research attention, the genomic alterations that occur in metastasis remain insufficiently understood, especially within Asian populations. Furthermore, the genomic information obtained from the primary tumor inadequately guides metastatic cancer treatment, highlighting the critical need for in-depth investigations into metastatic TNBC. Methods: We constructed the largest cohort of TNBC metastases (n = 296) among advanced TNBC patients treated at Fudan University Shanghai Cancer Center (FUSCC) between October 2018 and December 2020. Comprehensive DNA sequencing was conducted on the collected metastatic samples to analyze genomic alterations associated with treatment response. The underlying mechanisms of specific biomarkers were also explored. Results: We presented the genomic landscape of 296 TNBC metastases, encompassing mutant genes, mutation sites and copy number variations. Through multidimensional analysis, significant disparities in TNBC were observed between Western and Asian populations, primary and metastatic tumors, as well as different metastatic sites. Notably, our findings underscore the importance of sequencing TNBC metastases to guide precision therapy, which was associated with longer progression-free survival compared to physician-chosen treatments, shedding light on the pivotal clinical value of genomic studies in metastatic settings. Furthermore, efficacy analysis suggested that PKD1 mutations enriched in metastases mediated resistance to immunotherapy. These findings were further validated through three clinical trials (NCT03805399, NCT04129996, and NCT04395989). Mechanistic studies unveiled the involvement of PKD1 in TNBC immune evasion by upregulating CCL2, thereby facilitating the recruitment of M2-type tumor-associated macrophages. Conclusion: Our study emphasizes the critical significance and necessity of genomic profiling of metastases in guiding precision therapy for TNBC. Moreover, our findings reveal PKD1 as a novel and promising biomarker for immunotherapy. Citation Format: Xiu-Zhi Zhu, Yi-Fan Zhou, Yun-Yi Wang, Xiao-Hong Ding, Xi Jin, Zhi-Ming Shao, Yi-Zhou Jiang, Zhong-Hua Wang. Genomic characterization of triple-negative breast cancer metastases reveals PKD1 as a novel biomarker for immunotherapy [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 PO1-15-08.

Abstract PO1-03-05: Tolerance of adjuvant radiotherapy combined with pembrolizumab for triple negative breast cancer

Abstract BACKGROUND AND PURPOSE: The current standard-of-care management of locally advanced triple negative breast cancer (TNBC) is based on neoadjuvant chemo-immunotherapy with pembrolizumab, surgery, radiotherapy and adjuvant pembrolizumab. However, the safety of combining pembrolizumab with adjuvant breast radiotherapy has never been evaluated. This study evaluated the tolerance profile of concurrent pembrolizumab (P) with adjuvant radiotherapy (RT) in locally advanced TNBC patients. METHODS: This bicentric ambispective study included the first prospectively registered patients with non-metastatic TNBC treated with the KEYNOTE-522 regimen in our institution. They received P in combination with carboplatin and paclitaxel chemotherapy and a second chemotherapy with doxorubicin and cyclophosphamide, followed by surgery and locoregional RT with or without P as adjuvant treatment. RT was normo- or hypofractionated, for the breast or chest wall, with or without lymph node irradiation according to institutional guidelines. Adjuvant P was administered at a total dose of 1800 mg at 200 mg once every 3 weeks or 400 mg once every 6 weeks. The safety profile was evaluated during and after the end of RT (until the last contact) with CTCAE V.5 scale. RESULTS: A total of 55 patients (pts) were prospectively included between July 2021 and March 2023. The median age was 49 years (29-69). The median follow-up was 12 months ( range, 10-26). Of them, 27 (49%) did not receive P concomitantly with RT (RT-only group) because of neo-adjuvant treatment related toxicities, and 28 (51%) received P concomitantly with RT (P-RT group). There was no statistical difference in population and toxicity between the RT-only group and the P-RT group. Nine patients were diagnosed with cardiac toxicities before the beginning of the RT and did not receive P during the RT. No RT-induced grade ≥4 toxicities were observed. Early toxicities were mainly grade 1-2. Two grade 3 toxicities occurred (1 case of axillary pain in the P-RT group and 1 radiodermatitis in the RT-only group). No cardiac or pulmonary toxicities ≥grade 2 were observed with adjuvant therapy. The toxicity profile is given in table 1. DISCUSSION: In these series, the main cause of discontinuation of pembrolizumab was related to suspicion of cardiac adverse events occurring during the neoadjuvant treatment and related to the injection of pembrolizumab or of the chemotherapy. All myocarditis happened before radiotherapy and did not affect the administration of radiotherapy. In this context, the optimal radiotherapy technique and cardiac dose constraints after ICI-induced myocarditis is unknown and late cardiotoxicity studies will be needed to precise these points. Cardiac sparing techniques, such as deep-inspiration breath hold, proton therapy, or alternative positioning (such as isocentric lateral decubitus) could be considered. CONCLUSION: Adjuvant radiotherapy can be combined with pembrolizumab for TNBC patients without increasing the risk of radiation-induced adverse events, allowing maintaining a systemic treatment in these high-risk patients. Longer follow-up and prospective studies are needed to validate these results. Adjuvant treatment-related adverse events Citation Format: Youlia Kirova, Thaïs Tison, Pierre Loap, Emilie ARNAUD, Kim Cao, Solène Bringer, Manon Kissel, Safia Maaradji, Juliette Mainguene, Jean-Yves Pierga, Florence Lerebours, Anne Salomon, Mariana Mirabelle, Delphine Loirat, Francois-Clement Bidard. Tolerance of adjuvant radiotherapy combined with pembrolizumab for 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 PO1-03-05.

Predictive biomarkers of response and survival following immunotherapy with a PD-L1 inhibitor benmelstobart (TQB2450) and antiangiogenic therapy with a VEGFR inhibitor anlotinib for pretreated advanced triple negative breast cancer

In our phase Ib trial (ClinialTrials.gov Identifier: NCT03855358), benmelstobart (TQB2450), a novel humanized IgG1 antibody against PD-L1, plus antiangiogenic multikinase inhibitor, anlotinib, demonstrated promising antitumor activities in pretreated triple negative breast cancer (TNBC) patients. We conducted explorative analyses of genomic biomarkers to explore the associations with treatment response and survival outcomes. Targeted next generation sequencing (NGS) was undertaken toward circulating tumor DNA (ctDNA) collected from peripheral blood samples prior to the start of treatment and after disease progression. A total of 31 patients received targeted NGS and functional driver mutations in 29 patients were analyzed. The most frequent mutations were TP53 (72%), MLL3 (28%), and PIK3CA (17%). At a blood-based tumor mutational burden (bTMB) cutoff of 6.7 mutations per megabase, patients with low bTMB showed better response to anlotinib plus TQB2450 (50% vs. 7%, P = 0.015) and gained greater PFS benefits (7.3 vs. 4.1 months, P = 0.012) than those with high bTMB. At a maximum somatic allele frequency (MSAF) cutoff of 10%, a low MSAF indicated a better objective response (43% vs. 20%) as well as a significantly longer median PFS (7.9 vs. 2.7 months, P < 0.001). Patients with both low MSAF and low bTMB showed a notably better objective response to anlotinib plus TQB2450 (70% vs. 11%, P < 0.001) and a significantly longer median PFS (11.0 vs. 2.9 months, P < 0.001) than patients with other scenarios. Our findings support future studes and validation of MSAF and the combined bTMB-MSAF classification as predictive biomarkers of immune checkpoint inhibitor-based regimens in advanced TNBC patients.

Treatment patterns and healthcare resource utilization for triple negative breast cancer in the Brazilian private healthcare system: a database study

In Brazil, data on the management of triple negative breast cancer (TNBC) as well as the burden of the disease in terms of health care resources utilization (HCRU) are scarce. To characterize the treatment patterns and HCRU associated with the management of Brazilian TNBC patients from the perspective of the private healthcare setting. Patients with at least one claim related to ICD-10 C50 from January 2012 until December 2017, and at least one claim for breast cancer treatment were assessed from a private claims database and classified as early and locally advanced, or metastatic. All patients with hormone and/or targeted therapy were excluded. Three thousand and four patients were identified, of which 82.8% were diagnosed in early and locally advanced stages. For early and locally advanced TNBC patients, 75.3% were treated in an adjuvant setting, mainly with anthracycline regimes. For mTNBC patients, bevacizumab regimens were the main treatment prescribed. More than 48% of mTNBC patients were switched to a second line of treatment. HCRU was higher for mTNBC patients when compared to early and locally advanced patients, with higher costs for metastatic disease management. The treatment setting has little influence on the HCRU pattern or the cost of disease management. The highest burden of disease was observed for metastatic management.

Efficacy and safety of apatinib combined with dose-dense paclitaxel and carboplatin in neoadjuvant therapy for locally advanced triple-negative breast cancer: A prospective cohort study with propensity-matched analysis.

Optimizing neoadjuvant therapy for triple-negative breast cancer (TNBC) is still an urgent problem to be solved in the clinic. In this prospective cohort study, we investigated the efficacy and safety of apatinib combined with dose-dense paclitaxel and carboplatin (Apa+ddTCb) vs dose-dense paclitaxel plus carboplatin regimens alone (ddTCb) in neoadjuvant therapy for locally advanced TNBC. TNBC patients with clinical stage I-IIIC were enrolled to receive neoadjuvant Apa+ddTCb therapy. Enrolled patients who underwent surgery were matched with TNBC patients who received neoadjuvant ddTCb therapy by propensity score matching. 25 locally advanced TNBC patients were enrolled for neoadjuvant Apa+ddTCb therapy. The overall clinical ORR achieved 88.00% and DCR achieved 100.0% after 6 cycles. For 23 patients who received surgery, 69 TNBC patients who received neoadjuvant ddTCb therapy were matched. The pCR rate (60.9% vs 30.4%, P = .009) and the BCS rate (47.8% vs 21.7%, P = .016) were significantly improved in the Apa+ddTCb group. The incidence of adverse events, especially those related to antiangiogenic therapy, was higher in the Apa+ddTCb group. Further immunohistochemical analysis suggested that the expression levels of VEGF, EGFR, p-VEGFR2 and CK17 were significantly decreased after receiving neoadjuvant therapy in the Apa+ddTCb group, and the baseline CK17 expression level in non-pCR patients was significantly higher than those in the pCR patients. Progression-free survival was not reached yet. Apa+ddTCb regimen achieved an improved efficacy and acceptable adverse events compared with ddTCb regimen, which might be a promising strategy in the neoadjuvant therapy for locally advanced TNBC.

Effect of 1 H-NMR serum lipoproteins on immunotherapy response in advanced triple-negative breast cancer patients.

We previously reported the results of a phase II trial of anti-PD-1 antibody plus anti-vascular endothelial growth factor receptor 2 inhibitors and eribulin in heavily pretreated advanced triple-negative breast cancer with a favorable objective response rate (ORR) of 37.0% (NCT04303741). Here we report updated survival outcomes and serum metabolite changes of the study. Proton nuclear magnetic resonance spectroscopy was used to detect metabolite dynamics and explore biomarkers for response. We found that treatment-sensitive patients had higher very low-density lipoprotein-related metabolite expression at baseline. A lipid proteomics model consisting of six metabolites predicted ORR and progression-free survival at 6 months with area under the receiver operating characteristic curves of 0.88 and 0.87, respectively. Serum asparagine and sarcosine concentrations were significantly higher after treatment in treatment-resistant patients. In conclusion, we constructed a model consisting of six metabolites to identify patients who benefit more from the triplet treatment, and asparagine and sarcosine may be associated with treatment resistance.

Adding fasting-mimicking diet to first-line carboplatin-based chemotherapy is associated with better overall survival in advanced triple-negative breast cancer patients: A subanalysis of the NCT03340935 trial.

Severe calorie restriction, in the form of cyclic fasting or fasting-mimicking diets (FMDs), boosts the antitumor activity of cytotoxic chemotherapy in mouse models of triple-negative breast cancer (TNBC). This effect is mostly mediated by fasting/FMD-induced reduction of plasma glucose concentration and by a boost in antitumor immunity. However, clinical evidence that cyclic FMD may impact on the outcomes of advanced TNBC (aTNBC) patients is lacking. We compared the overall survival (OS) of 14 aTNBC patients receiving first-line carboplatin-gemcitabine plus cyclic FMD in the context of the NCT03340935 trial with the OS of 76 consecutive aTNBC patients treated with carboplatin-based chemotherapy alone at Fondazione IRCCS Istituto Nazionale dei Tumori. Multivariable Cox regression models were used to adjust the prognostic impact of FMD for other prognostic variables. Patients undergoing cyclic FMD in combination with carboplatin-gemcitabine had better OS when compared to patients receiving chemotherapy alone (median OS 30.3 months, 95% CI 18-NR, vs 17.2 months, 95% CI 15.3-25.1, log-rank P value .041). Multivariable analysis confirmed an association between FMD use and better OS (HR: 0.40; 95% CI: 0.19-0.86; P = .019) also after propensity score-based matching according to patient ECOG PS and the presence of de novo metastatic disease (HR: 0.41; 95% CI: 0.21-0.83; P = .013). Cyclic FMD in combination with first-line chemotherapy may improve clinical outcomes in aTNBC patients. Our study paves the way for conducting phase II trials to investigate if cyclic FMD can increase the antitumor activity/efficacy of chemotherapy or chemoimmunotherapy in patients with early-stage TNBC or aTNBC.

Atezolizumab and paclitaxel as first line therapy in advanced triple-negative breast cancer patients included in the French early access program

Following the results of the IMpassion130 trial, an early access program (EAP) was opened in France, allowing patients with PD-L1-positive advanced triple negative breast cancer (aTNBC) to receive a combination of paclitaxel and atezolizumab as first line therapy. This EAP was later discontinued when the IMpassion131 trial read out with negative results. We performed a retrospective multicentric analysis in patients who were prospectively enrolled in the French EAP. Efficacy and toxicity data were obtained on 64 patients treated from August 2019 to August 2020 in 10 French cancer centers. Median progression-free survival (PFS) and overall survival (OS) were 4.1 months (95% CI [3.0–5.8]) and 17.9 months (95% CI [12.4–NR]), respectively. The 6-months PFS rate was 28% (95% CI [16–40%]) (N = 18/64), while N = 33/64 patients (52%, 95% CI [38–63%]) experienced a tumor response. Exploratory subgroup analyses retrieved that corticosteroid use at inclusion in the EAP, before treatment initiation, was the only independent unfavorable prognostic factor for PFS (HR 2.7, 95% CI [1.3–5.6]). No new safety signal was observed. This real-life study, unique by its setting (EAP granted by anticipation and later withdrawn), suggests atezolizumab and paclitaxel has a limited efficacy in PD-L1-positive aTNBC, especially in patients receiving corticosteroids as comedication before treatment start.

High expression of MORC2 predicts worse neoadjuvant chemotherapy efficacy in triple negative breast cancer.

Tumor infiltrating lymphocytes (TILs) are closely related to the patients' prognosis. Recently, Microrchidia 2 (MORC2) has been documented as a prognostic and predictive biomarker in triple negative breast cancer (TNBC). To compare whether MORC2 is a better predictor than TILs, as well as clinicopathological parameters, in predicting the efficacy of neoadjuvant chemotherapy (NAC) in TNBC, we detected the expression of MORC2 on neoplastic cells through immunohistochemistry and quantified the stromal TILs through Hematoxylin-eosin staining on core biopsies from 50 locally advanced TNBC patients who underwent standard NAC. Among all the 50 patients, 28 (56%) cases had residual tumors, while the other 22 (44%) achieved pathologic complete response (pCR). In these studied patients, age and T-stage showed no correlation with pCR rate, while percentage of TILs, nodal involvement and expression of MORC2 on tumor cells showed significant association with pCR rate. Positive nodal involvement was correlation with worse pathologic response at multivariate analysis (P = .0036), and high TILs levels (≥50%) was positively associated with better NAC efficacy at univariate analysis (P = .002). Whereas high expression of MORC2 was statistically associated with worse pCR rate both at univariate (P < .001) and multivariate (P = .036) analysis. Our results indicate that MORC2 expression has a better predictive role in predicting the efficacy of NAC than TILs in TNBC patients.

A meta-analysis of application of PD-1/PD-L1 inhibitor-based immunotherapy in unresectable locally advanced triple-negative breast cancer.

Aims: The purpose of this study was to explore the efficacy of immunotherapy for patients with triple-negative breast cancer (TNBC). Materials & methods: Randomized clinical trials comparing immunotherapy with chemotherapy for advanced TNBC patients were included. Results: A total of sixarticles (3183 patients) were eligible for this meta-analysis. PD-1/PD-L1 inhibitor-based immunotherapy combined with chemotherapy can significantly increase the progression-free survival(hazard ratio [HR]=0.82;95% CI=0.76-1.14; p<0.001) of unresectable locally advanced or metastatic TNBC patients without effect on overall survival, compared with chemotherapy. Conclusion: PD-1/PD-L1 inhibitors-based immunotherapy can safely improve progression-free survival in patients with unresectable locally advanced or metastatic TNBC, but has no effect on overall survival.

A randomized phase II clinical trial of talazoparib maintenance therapy in patients with triple-negative breast cancer who showed platinum-sensitivity on first- or second-line platinum-based chemotherapy: KCSG BR21-10.

TPS1132 Background: A potent PARP inhibitor, talazoparib, demonstrated superior clinical activity compared to standard chemotherapy in germline BRCA1/2-mutant advanced breast cancer patients. However, the role of talazoparib treatment in BRCA1/2 wild-type triple-negative breast cancer (TNBC) patients remains undefined, although high incidence of homologous recombination deficiency (HRD) is one of the major characteristics of the TNBC. Previous studies indicated clinical responsiveness to platinum agents is a useful surrogate for HRD that may predict favorable PARP inhibitor response. Here, we present a phase II study to test talazoparib maintenance therapy in germline BRCA1/2 mutation unselected advanced TNBC patients after platinum-based chemotherapy. Methods: The KCSG BR21-10 study (NCT04755868) is a randomized double-blind placebo-controlled phase II clinical trial of talazoparib maintenance therapy in metastatic TNBC patients whose tumor showed platinum-sensitivity to first- or second-line platinum-based chemotherapy. The criteria for platinum-sensitivity were set as follows: remaining complete response (CR), partial response (PR), or stable disease (SD) after 6 to 9 tri-weekly doses or 18 to 27 weekly doses of platinum-based chemotherapy. The eligible TNBC patients are enrolled to the trial after completion of platinum-based therapy and 1:1 randomized to receive talazoparib (once daily 1.0 mg) or placebo maintenance therapy. The patient with any germline BRCA1/2 mutation status is eligible, and randomization stratification factors include line of platinum-based chemotherapy, response to platinum-based chemotherapy, and germline BRCA1/2 mutation status. The talazoparib/placebo maintenance treatment is initiated within 8 weeks after the last platinum chemotherapy. At the time of progression of disease, unblinding can be performed and patients in placebo arm may be eligible for crossover to talazoparib single treatment. The primary endpoint is progression-free survival (PFS) after randomization by RECIST 1.1, and the key secondary endpoints are overall survival, PFS2, objective response rate, adverse events by CTCAE 5.0 criteria, and quality of life. We also planned exploratory study to find predictive biomarker by tumor tissue and blood analysis. The median PFS from the randomization is expected to be 3 months in the placebo maintenance arm and we expect that talazoparib maintenance will improve PFS with hazard ratio of 0.65. It is predicted that a total of 206 patients (103 patients in each arm) are required with the α of 0.05 and power of 0.8 (1-β) by two-sided test, considering monthly 3% dropout rate. Currently, 23 of planned 206 patients have been enrolled. Clinical trial information: NCT04755868 .

Treatment patterns and clinical outcomes of newly diagnosed early-stage and locally advanced triple negative breast cancer (TNBC): A retrospective cohort analysis of national real-world data in England.

e12577 Background: TNBC patients have poorer survival outcomes when compared to other types of breast cancer, due to the lack of treatment options available and the aggressiveness of the disease. The current standard of care for early-stage TNBC is neoadjuvant pembrolizumab in combination with chemotherapy followed by pembrolizumab monotherapy after surgery (KEYNOTE-522), however prior to this treatment options and outcomes have been relatively limited compared to hormone receptor- and HER2- positive breast cancers. This study aimed to describe the treatment patterns and clinical outcomes of early-stage and locally advanced TNBC patients in England before the approval of KEYNOTE-522. Methods: In this retrospective cohort study, data from the English National Cancer Registration and Analysis Service databases (Cancer Registry, Systemic Anti-Cancer Therapy, Hospital Episode Statistics [HES], National Radiotherapy Dataset and Diagnostic Imaging Dataset) were used. Adults with a first record of primary early-stage or locally advanced TNBC (stage II – IIIb) between 01/01/2015 and 31/12/2018 were indexed. Treatment pathways and clinical outcomes were investigated over a maximum of 5-years follow-up period extending to December 2020. Outcomes were described descriptively. Results: A total of 3,475 patients met the inclusion criteria for the newly diagnosed TNBC cohort. 82.7% and 17.3% of patients were diagnosed at stage II and stage III respectively and, 83.3% were of white ethnicity, and 46.6% were node positive. Around 80% of patients had a primary surgery performed (i.e. a mastectomy or breast conserving surgery). Anthracyclines were the most common drug type used as a first regimen in both the neoadjuvant and adjuvant settings. During the follow up period, 37.7% and 15.3% of patients experienced locoregional or distant metastatic progression, respectively and 22.6% died. Median OS or EFS was not reached as &lt; 50% patients died within the 5-year follow up period. The 5-year OS and EFS rate was ~57% and ~60%, respectively. Increased healthcare resource utilisation (HCRU) with associated high costs was reported in the time periods post diagnosis. The mean number of TNBC-related inpatient stays was the highest in the 3 to 6 months following index; 3.77 (SD = 3.95), costing a total of £4,992,150.48 (per patient cost: £1,458.84 [£1918.76], mean [SD]). Conclusions: This is the first real world evidence study using the England NCRAS datasets to assess the outcomes of the early-stage and locally advanced TNBC population in England. Treatment plans were heterogenous in TNBC patients and probability of survival was poor. This highlights the need for improvement of the treatment options and thus clinical outcomes of this patient population.

A real-world study of immune checkpoint inhibitors in advanced triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer. Immune checkpoint inhibitors (ICIs) have been widely used to treat various tumors and have changed the landscape of tumor management, but the data from real-world studies of ICIs for TNBC treatment remain limited. The aim of this study was to evaluate the efficacy of ICIs in the treatment of patients with advanced TNBC in a real-world setting and to explore possible correlates. The clinical data of advanced TNBC patients who received ICI treatment in the Chinese People's Liberation Army (PLA) General Hospital were collected. Treatment responses, outcomes and adverse events (AEs) were assessed. Eighty-one patients were included in the study. The confirmed objective response rate (ORR) was 32.1%, and the disease control rate (DCR) was 64.2%. The median progression-free survival (PFS) was 4.2 months, and the median overall survival (OS) was 11.0 months. PFS and OS were longer in patients who achieved clinical benefit from ICIs and shorter in patients who received later-line ICIs and higher levels of inflammation; specifically, patients with higher TILs had longer PFS. Overall AEs were tolerable. ICIs are effective in the treatment of advanced TNBC, and the adverse reactions are tolerable. A panel of biomarkers including LDH, ALP, and bNLR were identified to predict the efficacies of ICIs in TNBC treatment.

Potential predictive value of circulating tumor DNA (ctDNA) mutations for the efficacy of immune checkpoint inhibitors in advanced triple-negative breast cancer.

Background: In recent years, tumor immunotherapy has become a viable treatment option for triple negative breast cancer (TNBC). Among these, immune checkpoint inhibitors (ICIs) have demonstrated good efficacy in advanced TNBC patients with programmed death-ligand 1 (PD-L1) positive expression. However, only 63% of PD-L1-positive individuals showed any benefit from ICIs. Therefore, finding new predictive biomarkers will aid in identifying patients who are likely to benefit from ICIs. In this study, we used liquid biopsies and next-generation sequencing (NGS) to dynamically detect changes in circulating tumor DNA (ctDNA) in the blood of patients with advanced TNBC treated with ICIs and focused on its potential predictive value. Methods: From May 2018 to October 2020, patients with advanced TNBC treated with ICIs at Shandong Cancer Hospital were included prospectively. Patient blood samples were obtained at the pretreatment baseline, first response evaluation, and disease progression timepoints. Furthermore, 457 cancer-related genes were evaluated by NGS, and patients' ctDNA mutations, gene mutation rates, and other indicators were determined and coupled with clinical data for statistical analysis. Results: A total of 11 TNBC patients were included in this study. The overall objective response rate (ORR) was 27.3%, with a 6.1-month median progression-free survival (PFS) (95% confidence interval: 3.877-8.323months). Of the 11 baseline blood samples, 48 mutations were found, with the most common mutation types being frame shift indels, synonymous single-nucleotide variations (SNVs), frame indel missenses, splicing, and stop gains. Additionally, univariate Cox regression analysis revealed that advanced TNBC patients with one of 12 mutant genes (CYP2D6 deletion and GNAS, BCL2L1, H3F3C, LAG3, FGF23, CCND2, SESN1, SNHG16, MYC, HLA-E, and MCL1 gain) had a shorter PFS with ICI treatment (p < 0.05). To some extent, dynamic changes of ctDNA might indicate the efficacy of ICIs. Conclusion: Our data indicate that ICI efficacy in patients with advanced TNBC may be predicted by 12 mutant ctDNA genes. Additionally, dynamic alterations in peripheral blood ctDNA might be used to track the effectiveness of ICI therapy in those with advanced TNBC.

Abstract P2-16-03: The Speckle-type POZ protein (SPOP) inhibits breast cancer malignancy by destabilizing oncogene TWIST1

Abstract Epithelial-mesenchymal transition (EMT) inducing transcription factor TWIST1 plays a vital role in cancer metastasis. How the tumor-suppressive E3 ligase, Speckle-type POZ protein (SPOP), regulates TWIST1 in breast cancer remains unknown. In this study, we report that SPOP physically interacts with, ubiquitinates, and destabilizes TWIST1. SPOP promotes K63-and K48-linked ubiquitination of TWIST1, predominantly at K73, thereby suppressing cancer cell migration and invasion. Silencing SPOP significantly enhances EMT, which accelerates breast cancer cell migration and invasiveness in vitro and lung metastasis in vivo. Clinically, SPOP is negatively correlated with the levels of TWIST1 in highly invasive breast carcinomas. Reduced SPOP expression, along with elevated TWIST1 levels, is associated with poor prognosis in advanced breast cancer patients, particularly those with metastatic triple-negative breast cancer (TNBC). Taken together, we have disclosed a new mechanism linking SPOP to TWIST1 degradation. Thus SPOP may serve as a prognostic marker and a potential therapeutic target for advanced TNBC patients. Citation Format: Chunli Wei, Yun Liu, Xiaoyan Liu, Jingliang Cheng, Jiewen Fu, Xiuli Xiao, Robb E Moses, Xiaotao Li, Junjiang Fu. The Speckle-type POZ protein (SPOP) inhibits breast cancer malignancy by destabilizing oncogene TWIST1 [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 P2-16-03.

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&amp;lt; 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&amp;lt; 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&amp;lt; 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.

Efficacy and Safety of First-line Carboplatin-paclitaxel and Carboplatin-gemcitabine in Patients With Advanced Triple-negative Breast Cancer: A Monocentric, Retrospective Comparison

BackgroundPlatinum-based chemotherapy is widely used in patients with advanced triple-negative breast cancer (TNBC). However, the most effective platinum-based combination in the first-line treatment setting remains unclear. Materials and MethodsWe evaluated the efficacy of first-line carboplatin-paclitaxel (CP) or carboplatin-gemcitabine (CG) combinations in advanced TNBC patients treated between April 2007 and April 2021. CP and CG were compared in terms of progression-free survival (PFS), overall survival (OS), and incidence of adverse events (AEs). Multivariable Cox Models were used to adjust the efficacy of CP versus CG for clinically relevant covariates. ResultsOf 88 consecutive advanced TNBC patients receiving first-line carboplatin-based doublets, 56 (63.6%) received CP and 32 (36.4%) CG. After adjusting for clinically relevant variables, patients receiving CG had significantly better PFS when compared to CP-treated patients (HR: 0.49 (95% CI, 0.27-0.87), P value 0.014). Of note, CG was associated with better PFS only among patients previously treated with taxanes in the (neo)adjuvant setting (HR: 0.39; 95% CI, 0.21-0.75), but not in patients not exposed to taxanes (HR: 1.20; 95% CI, 0.37-3.88). CG was also independently associated with better OS when compared to CP (HR: 0.31 (95% CI: 0.15-0.64), P value 0.002). Overall, grade 3-4 AEs were more common in patients treated with CG than in patients treated with CP (68.8% vs. 21.4%, P value .009). ConclusionCG and CP are effective and well tolerated first-line platinum doublets in advanced TNBC patients. CG could be more effective than CP in patients previous exposed to taxanes despite worse toxicity profile.