Treatment Of Metastatic Triple-negative Breast Cancer Research Articles

A self-targeting MOFs nanoplatform for treating metastatic triple-negative breast cancer through tumor microenvironment remodeling and chemotherapy potentiation

Triple-negative breast cancer (TNBC) is the most aggressive and fatal subtype of breast cancer with disappointing treatment and high mortality. Tumor microenvironment (TME) plays an important role in the invasion and metastasis of TNBC through multiple complex processes. Most anti-metastatic therapies only focus on cancer cells themselves or interfering with single factors of the metastasis process, which is often related to poor outcomes. Thus, effective TNBC treatment relies on regulating multiple key metastasis-related aspects of the TME. Herein, a self-targeting Metal-Organic Frameworks (MOFs) nanoplatform (named as MTX-PEG@TPL@ZIF-8) was designed to improve treatment of TNBC through tumor microenvironment remodeling and chemotherapy potentiation. The self-targeting MOF nanoplatform is consist of ZIF-8 nanoparticles loaded triptolide (TPL) and followed by the coating with methotrexate-polyethylene glycol conjugates (MTX-PEG). Due to MTX’s affinity for the overexpressed folate receptor on tumor cell surfaces, MTX-PEG@TPL@ZIF-8 enables effective accumulation and deep penetration in the tumor area by an MTX-mediated self-targeting strategy. This MOF nanoplatform could promptly release the medication after penetrating the tumor cell, due to pH-triggered degradation. Its anti-metastasis mechanism is to inhibit tumor invasion and metastasis by down-regulating the expression of Vimentin, MMP-2 and MMP-9 and increasing the expression of E-cadherin, upregulation of cleaved caspase-3 and cleaved caspase-9 protein expression promote the apoptosis of tumor cells, thereby reducing their migration. It also downregulated the expression of VEGF and CD31 protein to inhibit the generation of neovascularization. Overall, these findings suggest the self-targeting MOF nanoplatform offers new insights into the treatment of metastatic TNBC by TME remodeling and potentiating chemotherapy.

Abstract PO1-18-07: Phase I trial of combination pembrolizumab and ruxolitinib in metastatic triple negative breast cancer

Abstract BACKGROUND: The amplification of genes PDL-1, PDL-2, and JAK2 on chromosome 9p24, known as the PDJ amplicon, has been identified in 15% of triple negative breast cancer (TNBC) and is associated with tumor infiltrating lymphocytes and elevated JAK2 mRNA, suggesting a coordinated inflammatory response in TNBC. Adding pembrolizumab to chemotherapy in KEYNOTE trials 355 and 522 has validated the use of PD-1 blockade in TNBC and redefined the standard of care. Despite preclinical data suggesting a role for targeting the IL- 6/JAK2/STAT3 pathway, the JAK1/JAK2 inhibitor ruxolitinib has not shown efficacy as a single Agent in breast cancer. This is the first phase I clinical trial evaluating the combination of pembrolizumab and ruxolitinib in the treatment of metastatic TNBC. METHODS: We conducted a phase I clinical trial with accrual from 2018 to 2023 at Mayo Clinic Arizona. Patients (n=12) received 200 mg of IV pembrolizumab per cycle (every 3 weeks) with 3+3 dose escalation of oral ruxolitinib twice a day (dose level 0: 10 mg PO BID, level 1: 15 mg PO BID, level 2: 20 mg PO BID). The primary endpoint was to determine the maximum tolerated dose (MTD) of ruxolitinib and secondary endpoints were treatment safety and efficacy. Clinical response was assessed by computed tomography of the chest, abdomen, and pelvis every 3 cycles. PD-L1 expression in tumor was measured by immunohistochemistry (IHC). The effect of the combined therapies on T and B cell populations were assessed by flow cytometry and antibody profiling of 695 tumor antigens and 8 viral antigens by nucleic acid protein programmable array. RESULTS: Twelve female patients with chemotherapy refractory metastatic TNBC were treated on study. All received 200 mg IV pembrolizumab every cycle. Due to rapid disease progression of three patients early after treatment initiation, eligibility was restricted to prohibit patients with extensive pulmonary disease or elevated LDH. Those patients were excluded from efficacy or correlative analysis. The most common toxicities were transaminitis (n=12), anemia/leukopenia (n=12), and fatigue (n=9). The majority of adverse events were grade 1 and occurred at dose level 2. There were 5 adverse events grade 3 or higher: respiratory or thoracic complications (n=3), hypertension (n=1), and abdominal pain (n=1), but MTD was not established. The median number of cycles was 4 for each dose level (range n=2.0-9.0) and the median time to progression was 3 months (range n=1.4-6.3). No patient had tumor response by RECIST v1.1 criteria and there was no association of disease stability with PD-L1 tumor expression by IHC. Circulating antibodies to tumor antigens remained stable, and viral-specific antibodies mildly decreased by month 2 in all patients at dose levels 0 and 1. Of the 7 patients reactive to TRIM21 autoantibodies, 2 patients had a transient increase at 2 months. CONCLUSIONS: The combination of pembrolizumab with ruxolitinib was well tolerated at all dose levels, and the number but not the severity of adverse events increased with higher ruxolitinib dose. Two of six patients in dose level 0 and 1 had stable disease for six months on treatment, suggesting that the lower dose levels of ruxolitinib (i.e. 10 mg PO BID) may have more activity in combination with pembrolizumab. Citation Format: Anelia Kassi, Jacqueline Carmona, Sarah M. Green, Heidi Kosiorek, Michael T. Barrett, Barbara A. Pockaj, Donald Northfelt, Karen S. Anderson. Phase I trial of combination pembrolizumab and ruxolitinib in 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 PO1-18-07.

Update on Classic and Novel Approaches in Metastatic Triple-Negative Breast Cancer Treatment: A Comprehensive Review.

Triple-negative breast cancer (TNBC) accounts for almost 15% of all diagnosed breast cancers and often presents high rates of relapses and metastases, with generally poor prognosis despite multiple lines of treatment. Immunotherapy has radically changed the approach of clinicians towards TNBC in the last two to three years, even if targeted and specific therapeutic options are still missing; this unmet need is further justified by the extreme molecular and clinical heterogeneity of this subtype of breast cancer and by the weak response to both single-agent and combined therapies. In March 2023, the National Comprehensive Cancer Network (NCCN), the main association of cancer centers in the United States, released the last clinical practice guidelines, with an update on classic and novel approaches in the field of breast cancer. The purpose of this comprehensive review is to summarize the latest findings in the setting of metastatic TNBC treatment, focusing on each category of drugs approved by the Food and Drug Administration (FDA) and included in the NCCN guidelines. We also introduce part of the latest published studies, which have reported new and promising molecules able to specifically target some of the biomarkers involved in TNBC pathogenesis. We searched the PubMed and Scopus databases for free full texts reported in the literature of the last 5 years, using the words "triple-negative breast cancer" or "TNBC" or "basal-like". The articles were analyzed by the authors independently and double-blindly, and a total of 114 articles were included in the review.

A single-arm phase II clinical trial of anlotinib combined with chemotherapy for the treatment of metastatic triple-negative breast cancer.

Anlotinib is a novel oral small-molecule tyrosine kinase inhibitor (TKI), which can inhibit angiogenesis. The purpose of this study was to evaluate the efficacy and safety of anlotinib combined with chemotherapy in patients with metastatic triple-negative breast cancer (TNBC). This phase II clinical trial included 40 patients with metastatic TNBC who had previously received anthracycline and/or taxane treatment. All patients received anlotinib combined with chemotherapy. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR), disease control rate (DCR) and safety. During May 1, 2019 and April 30, 2022, there were 40 patients enrolled in this study. The median PFS and median OS were 8.8 months (95% confidence interval [CI] 6.5-11.1 months) and 19.0 months (95% CI, 12.1-25.9 months), respectively. The ORR, CBR and DCR were 40.0% (16/40), 85.0% (34/40) and 95.0% (38/40), respectively. Cox univariate and multivariate analyses demonstrated that having more than 3 metastatic sites (p = 0.001; p = 0.020) was an independent and meaningful unfavorable prognostic factor for PFS. 37.5% of patients had grade 3 to 4 treatment-related adverse events (TRAEs). The grade 3 to 4 TRAEs included neutropenia (22.5%), leukopenia (20.0%), secondary hypertension (10.0%), hand-foot syndrome (5.0%), vomiting (5.0%), proteinuria (5.0%) and thrombocytopenia (2.5%). None of the patients withdrew from the study or died due to TRAEs. In this single-arm study, the treatment of metastatic TNBC with anlotinib combined with chemotherapy showed certain efficacy, and its toxicity was acceptable.

Abstract P1-08-04: Therapeutic Advances in Metastatic Triple-Negative Breast Cancer: Identifying and Reducing Clinician Knowledge Gaps

Abstract Background: Characterization of the aggressive biology of triple-negative breast cancer (TNBC), defined by its lack of estrogen receptor, progesterone receptor, and human epidermal growth factor 2 (HER2) expression, has led to the development of more effective treatments for patients, but research indicates that clinicians face challenges in maintaining a working knowledge of evolving data. This study was conducted to determine what learning gaps exist in the area of therapeutic advances in TNBC and to investigate whether an online, case-based continuing medical education (CME)/nursing continuing professional development (NCPD)–approved activity could address gaps in clinicians’ knowledge regarding the personalized care of patients with metastatic TNBC. Methods: The CME/NCPD-approved live webinar series titled Metastatic Triple-Negative Breast Cancer: Applying Treatment Advances to Personalized Care was presented by Sara A. Hurvitz, MD, FACP, on July 13 and July 15, 2021, and was made accessible as a CME/NCPD-approved enduring webinar archive starting on July 23, 2021. Learners participated in a 1-hour activity that highlighted emerging therapeutic targets in TNBC, with an emphasis on current challenges and new opportunities in the management of metastatic disease. Learners completed a repeated-pairs pre- and post-activity assessment consisting of case-based questions that gauged their ability to apply emerging data to clinical decision making. Baseline knowledge gaps and subsequent learning gains were calculated based on percentages of learners obtaining correct responses on the pre- and post-activity assessments. Significance was assessed using a chi-squared test. In addition, learners reported self-perceived gains in confidence and competence using 5-point Likert scale questions. Results: As of June 28, 2022, 811 clinicians had completed the activity for credit; 62 learners participated in the live webinar, while 749 participated in the online enduring activity. Baseline assessment data revealed gaps in knowledge regarding emerging actionable targets and management of treatment-related adverse events (Table 1). Learners participating in the enduring activity scored an average of 43% on pretest topics; after completing the activity, the posttest average rose to 92%. The activity resulted in significant gains in knowledge and competence related to these topics, with P < 0.0001 for all learning gains. Upon completion of the activity, 86% of learners self-reported that knowledge acquired from this activity would be utilized to improve the outcomes of their patients, and 86% of learners self-reported that based on the information learned during the activity, they felt more confident in treating patients with metastatic TNBC. Conclusions: These data indicate that a substantial knowledge gap exists regarding the latest developments in the treatment of metastatic TNBC. They also demonstrate that online, case-based CME/NCPD-approved activities can result in statistically significant improvements in clinicians’ knowledge of therapeutic advances and management of treatment-related adverse events for patients with metastatic TNBC. Acknowledgements: This activity was supported by an independent educational grant from Merck. Table 1. Baseline Knowledge Gaps and Post-Activity Learning Gains. Citation Format: Elizabeth J. Heller, Keira Smith, Sarah L. Williams. Therapeutic Advances in Metastatic Triple-Negative Breast Cancer: Identifying and Reducing Clinician Knowledge Gaps [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 P1-08-04.

Abstract 954: Combined treatment of γ-tocotrienol, and vitamin D3 synergistically inhibits breast cancer cell proliferation, migration, and epithelial-to-mesenchymal transition (EMT)

Abstract Metastatic breast cancer is a leading cause of death of women in the United States. The metastatic process involves epithelial cells losing their cellular polarity, adhesion to the basement membrane, and acquiring migratory and invasive properties. Metastatic epithelial cells take on a mesenchymal phenotype, hence this process is termed epithelial-to-mesenchymal transition (EMT). EMT is characterized by a reduction in epithelial cell marker expression (E-cadherin, cytokeratin 8, and cytokeratin 18), and an increased expression of mesenchymal cell markers (N-cadherin, vimentin, and fibronectin). Previous studies have demonstrated that dietary intake of γ-tocotrienol and/or vitamin D3 may provide benefit in the preventing the growth and development of metastatic breast cancer. γ-Tocotrienol is a natural isoform of vitamin E that shows potent anticancer activity against a variety of cancer cell types at treatment doses that have little or no effect on normal cell growth or viability. Vitamin D3 has also been shown to display potent antiproliferative and antiangiogenic activity against human breast cancer cells, particularly triple negative breast cancers. Studies were conducted here to examine the effects of γ-tocotrienol and vitamin D3 given alone or in combination on MDA-MB-231 triple negative breast cancer (TNBC) cellular proliferation, migration, and epithelial to mesenchymal transition. Treatment with 10-16 µM γ-tocotrienol or 20-40 nM vitamin D3 induced a significant dose-responsive decrease in MDA-MB-231 growth after a 4-day culture period. Combined treatment with sub-effective doses of γ-tocotrienol (8 μM) and vitamin D3 (10 nM) induced a synergistically inhibition of MDA-MB-231 cell growth, as determined isobologram analysis. Studies using the matrigel invasion assay showed that similar combination treatment with subeffective doses of γ-tocotrienol and vitamin D3, significantly inhibited MDA-MB-231 motility. These effects appear to result from a reversal in EMT. Western blot analysis shows that combined treatment resulted in an increased expression of the epithelial cell markers E-cadherin, cytokeratins 8 and cytokeratins 18 and a corresponding reduction in mesenchymal cell markers N-cadherin and vimentin. Taken together, these findings indicate that combined treatment with subeffective doses of γ-tocotrienol and vitamin D3 synergistically inhibit TNBC MDA-MB-231 breast cancer cell growth, viability, motility, and induced a reversal of EMT. These findings strongly suggest that combined γ-tocotrienol and vitamin D3 treatment may provide significant benefits in the treatment of metastatic TNBC in women. This study was supported in part by funding from the Louisiana Cancer Foundation. Citation Format: Md. Rafi Anwar, Taylor A. Hurst, Paul W. Sylvester. Combined treatment of γ-tocotrienol, and vitamin D3 synergistically inhibits breast cancer cell proliferation, migration, and epithelial-to-mesenchymal transition (EMT) [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 954.

Abstract 5399: Synergistic combination nanomedicine of doxorubicin and oligo hyaluronic acid inhibits DNA damage repair and overcomes drug resistance in metastatic triple-negative breast cancer

Abstract Background: Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer subtype. Despite the early response to chemotherapy, high incidence of recurrence leads to short overall survival and poor prognosis. Native hyaluronic acid (HA) interacts with CD44 and receptors for hyaluronan mediated motility (RHAMM) overexpressed in TNBC mediating chemo-resistance and metastasis. In contrast, oligomeric HA (oHA) can disrupt HA-CD44/RHAMM interactions and attenuate oncogenic and pro-metastatic pathways, such as the mitogen-activated protein kinase/extracellular-signal-regulated kinase (MAPK/ERK) pathway, reducing downstream DNA repair and drug resistance markers. Our previous work demonstrated that oHA can exert synergistic anti-tumor and anti-metastatic effects when combined with doxorubicin (DOX) and co-loaded in an integrin-targeted iRGD-modified nanoparticle system (iRGD-DOX-oHA-PLNs). This study aims to investigate the inhibitory effect of iRGD-DOX-oHA-PLNs on both DNA single-strand break (SSB) and double-strand break (DSB) repair proteins and drug efflux pumps responsible for multidrug resistance to enhance DOX efficacy in breast cancer gene 1 (BRCA1) mutant and non-mutant TNBC. Methods: The cytotoxicity of DOX, oHA and their combinations in free solution or in nanoparticles was evaluated by clonogenic assay in human MDA-MB-231-luc-D3H2LN and MDA-MB-436 (BRCA1 mutant) TNBC cells. The in vitro expression of a DNA DSB marker, DNA repair markers, and drug efflux pump P-glycoprotein (P-gp) were measured by Western blot. The in vivo expression level of BRCA1 and Rad51 in an orthotopic TNBC mouse model was determined by immunohistochemical staining. Results: The combination of DOX-oHA showed synergism against both BRCA1 mutant and non-mutant TNBC cells. The iRGD-DOX-oHA-PLNs induced great increases in DNA DSBs demonstrated by the highest γH2AX level compared to other treatment groups. These nanoparticles also showed inhibitory effects on the expression of both DNA SSB repair protein (poly (ADP-ribose) polymerase) and DNA DSB repair proteins (Rad50 and Rad51), contributing to the enhanced efficacy of chemotherapy. The immunohistochemical staining of tumor tissues indicated lower levels of BRCA1 and Rad51 after iRGD-DOX-oHA-PLN treatment than the formulation without oHA, attributable to the effect of intracellularly delivered oHA on limiting the MAPK signaling. Additionally, iRGD-DOX-oHA-PLNs reduced the expression of the drug efflux pump P-gp as compared to DOX treatment groups without oHA. Conclusion: The co-delivery of oHA and DOX in the iRGD-DOX-oHA-PLNs efficiently blocked DNA damage repair and down-regulated the drug efflux pump P-gp, thus improving the efficacy of DOX. Collectively, this nanoparticle system could be a promising option for metastatic TNBC treatment. Citation Format: Pei Zhi, Ibrahim Alradwan, Tian Zhang, HoYin Lip, Abdulmutalib Zetrini, Chunsheng He, Jeffery Henderson, Andrew Michael Rauth, Xiao Yu Wu. Synergistic combination nanomedicine of doxorubicin and oligo hyaluronic acid inhibits DNA damage repair and overcomes drug resistance in metastatic 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 5399.

Treatment advances in metastatic triple-negative breast cancer (TNBC): Addressing the knowledge gap.

e23006 Background: The dearth of effective treatment options for patients with metastatic TNBC has enabled the rapid development of more effective treatments for this condition, but research indicates that clinicians face challenges in maintaining a working knowledge of evolving data. This study was conducted to determine if an online, case-based continuing medical education (CME)/nursing continuing professional development (NCPD)–approved activity could identify and address gaps in clinicians’ knowledge regarding the personalized care of patients with metastatic TNBC. Methods: The activity, Metastatic Triple-Negative Breast Cancer: Applying Treatment Advances to Personalized Care, chaired by Sara A. Hurvitz, MD, FACP, was made accessible starting on July 23, 2021. Learners participated in a 1-hour activity that highlighted emerging therapeutic targets in TNBC, with an emphasis on current challenges and new opportunities in the management of metastatic disease. Learners completed a repeated-pairs pre- and post-activity assessment consisting of case-based questions that gauged their ability to apply emerging data to clinical decision making. Knowledge gaps and learning gains were calculated based on percentages of learners obtaining correct responses on the pre- and post-activity assessments. Significance was assessed using a chi-squared test. Results: As of February 2, 2022, 632 clinicians had completed the activity for credit. Baseline assessment data revealed gaps in knowledge regarding emerging actionable targets and management of treatment-related adverse events (Table). The activity resulted in significant gains in knowledge and competence related to these topics, with P < 0.0001 for all learning gains. Conclusions: These data indicate that a substantial knowledge gap exists regarding the latest developments in the treatment of metastatic TNBC. They also demonstrate that online, case-based CME/NCPD-approved activities can result in statistically significant improvements in clinicians’ knowledge of therapeutic advances and management of treatment-related adverse events for patients with metastatic TNBC. Acknowledgements: This activity was supported by an independent educational grant from Merck.[Table: see text]

Treatment for Triple-Negative Breast Cancer: An Umbrella Review of Meta-Analyses.

PurposeIn recent years, many meta-analyses of triple-negative breast cancer (TNBC) treatment have been published; however, these studies still lack systematic summary. Therefore, the aim of this study is to summarize and evaluate the evidence level and efficacy of treatment for TNBC.Materials and MethodsRetrospective and prospective studies on treatment of TNBC were searched in the PubMed, Embase, and Cochrane Library databases. The literature search deadline was June 30, 2021. Two investigators independently screened the literature and extracted the data. In addition, the joint World Health Organization–United Nations Food and Agriculture Organization expert consultation was used to evaluate the validity of the evidence.ResultsA total of 28 meta-analyses were included in this study. The treatment interventions for TNBC mainly included surgery, chemotherapy (CT), radiotherapy, molecular targeted therapy, immunotherapy, zoledronic acid, and gonadotropin-releasing hormone (GnRH) analog. Platinum improves the pathological complete response (PCR) rate of patients treated with neoadjuvant chemotherapy (NACT), the objective remission rate (ORR) and overall survival (OS) in patients with metastatic triple-negative breast cancer. Capecitabine improves disease-free survival (DFS) and OS in patients treated with adjuvant CT. Bevacizumab was added to NACT to improve the PCR rate in patients. Immunotherapy improves the PCR rate in patients treated with NACT. The improvement in PCR rate in patients with high Ki67 expression treated with neoadjuvant therapy is highly suggestive. Other interventions had suggestive or weak evidence.ConclusionAmong the strategies for treating TNBC, platinum, bevacizumab, and immunotherapy can lead to better PCR rates as part of a NACT regimen. Capecitabine as adjuvant CT and platinum in the treatment of metastatic TNBC can benefit patients’ survival. However, the effectiveness of other interventions for TNBC is not yet clear. Further research is needed in the future to obtain more reliable clinical evidence.

Abstract OT2-01-03: Trial in progress: Phase 2 study of intratumoral plasmid interleukin-12 (tavokinogene telseplasmid; TAVO™) plus electroporation in combination with pembrolizumab with or without chemotherapy in patients with inoperable locally advanced or metastatic triple-negative breast cancer (KEYNOTE-890/OMS-I141)

Abstract BACKGROUND: Interleukin-12 (IL-12) is a potent immunoregulatory cytokine that plays a key role in the crosstalk between innate (dendritic, macrophage, and natural killer) and adaptive (T and B) cells promoting anti-tumor immune responses. DNA plasmid-based IL-12 delivered to accessible tumors by intratumoral injection and electroporation (TAVO-EP) has been shown to induce activation of innate and adaptive tumor-infiltrating and peripheral immune cells, regression of treated and distant untreated lesions (abscopal effect), and expression of PD-L1 in patients with melanoma or triple-negative breast cancer (TNBC), without the systemic toxicity that has limited therapeutic use of IL-12 historically. The combination of TAVO-EP and pembrolizumab has demonstrated durable responses in melanoma patients with immunologically “cold” tumors or with prior progression on anti-PD1 therapy. Early clinical data indicate similar potential for eliciting strengthened immunogenic responses in TNBC. KEYNOTE-890 (OMS-I141) is a Phase 2 study in patients with metastatic TNBC to evaluate the safety and efficacy of TAVO-EP + pembrolizumab in the second-line or later (2L+) treatment setting (Cohort 1) or TAVO-EP + pembrolizumab + chemotherapy in the first-line (1L) setting (Cohort 2). Cohort 1 data are presented in a separate abstract. Enrollment in Cohort 2 is ongoing. METHODS: Cohort 2 of this Phase 2, open-label, multicenter study will be assessing the safety and efficacy of TAVO-EP in combination with pembrolizumab and chemotherapy as a first-line treatment for metastatic TNBC. Eligible patients are adults with metastatic TNBC (ER and PR staining <10%, HER2 0 to 1+ or [F]ISH-negative), no prior systemic therapy for advanced disease (neo/adjuvant therapy allowed if at least 6-month disease-free interval from last treatment), measurable disease by RECIST v1.1, at least one lesion accessible for TAVO-EP treatment, and biopsy tissue available for post-hoc central determination of PD-L1 expression. Patients will receive pembrolizumab (200 mg IV) every 3 weeks, TAVO-EP (0.5 mg/mL at dose volume of ~1/4 lesion volume) on Days 1, 5, and 8 every 6 weeks, and nab-paclitaxel (100 mg/m2 IV) on Days 1, 8, and 15 every 4 weeks. Additional chemotherapy options may be introduced in future protocol amendments. Tumor assessments will be performed every 12 weeks. On-study biopsies will be collected approximately 3 weeks after start of treatment and at disease progression. The primary endpoint will be ORR assessed by blinded independent review per RECIST v1.1. Additional endpoints will include safety and tolerability, duration of response, immune ORR, progression-free survival (PFS), immune PFS, disease control rate, and overall survival. Planned enrollment in Cohort 2 is 40 patients. Based on positive efficacy data in Cohort 1, additional cohorts are being planned and will be presented. ClinicalTrials.gov: NCT03567720 Citation Format: Melinda Telli, Bianca Devitt, Katharine Cuff, Shaveta Vinayak, Rita Nanda, Alberto J. Montero, Rina Hui, David A. Canton, Christopher Twitty, Sunny Xie, Donna Bannavong, Bridget O'Keeffe, Sandra Aung, Rohit Joshi. Trial in progress: Phase 2 study of intratumoral plasmid interleukin-12 (tavokinogene telseplasmid; TAVO™) plus electroporation in combination with pembrolizumab with or without chemotherapy in patients with inoperable locally advanced or metastatic triple-negative breast cancer (KEYNOTE-890/OMS-I141) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-01-03.

BEGONIA: Phase 1b/2 study of durvalumab (D) combinations in locally advanced/metastatic triple-negative breast cancer (TNBC)—Initial results from arm 1, d+paclitaxel (P), and arm 6, d+trastuzumab deruxtecan (T-DXd).

1023 Background: Chemotherapy with immune checkpoint inhibitors can improve outcomes vs chemotherapy alone in patients (pts) with metastatic TNBC; however, many still have poor clinical outcomes. BEGONIA is an ongoing 2 part, multicenter, multiarm, open-label platform study evaluating safety and efficacy of D (anti–PD-L1)+P and D±P combined with novel therapies as first-line (1L) treatment for metastatic TNBC (NCT03742102). We report initial results from Part 1 of Arm 1, D+P, and Arm 6, D+T-DXd, an antibody-drug conjugate comprising an anti-HER2 antibody, tetrapeptide-based cleavable linker, and topoisomerase I inhibitor payload. Methods: Eligible pts had untreated unresectable locally advanced or metastatic TNBC. Pts with HER2-low–expressing tumors (IHC 2+/ISH–, IHC 1+/ISH–, or IHC 1+/ISH untested) per local testing were assigned to the D+T-DXd arm. Pts received D (1500 mg IV Q4W)+P (90 mg/m2 IV Day 1, 8, 15 Q4W) in Arm 1 and D (1120 mg IV)+T-DXd (5.4 mg/kg IV) Q3W in Arm 6, until progression or unacceptable toxicity. Primary objectives are safety and tolerability. Secondary endpoints include objective response rate (ORR), duration of response (DoR), and progression-free survival (PFS). Tumors were assessed Q8W (D+P) or Q6W (D+T-DXd). The first 6 pts treated with D+T-DXd were evaluated for dose-limiting toxicities (DLTs), with additional pts enrolled if D+T-DXd was tolerated. Study arms are noncomparable due to differing eligibility criteria, treatments, and data maturity. Results: Arm 1 D+P (data cutoff Sep 2020): 23 pts received D+P (7 ongoing); 2 discontinued D+P due to AEs. Median follow-up time was 16.6 (range 8.5–19.8) mos. Any Grade 3/4 AEs and SAEs were experienced by 10 (44%) and 1 (4%) pts, respectively. D dose was delayed for 7 (30%) pts. Confirmed ORR was 13/23 (57%) with 54% of those remaining in response at 12 mos (median DoR not reached). Median PFS was 7.3 (95% CI 5.4–13.8) mos in the D+P arm. Arm 6 D+T-DXd (data cutoff Nov 2020): 11 pts received D+T-DXd to date (all ongoing). Median follow-up time was 2.3 (0–6) mos. Any Grade 3/4 AEs and SAEs were experienced by 4 (36%) and 1 (9%) pts, respectively. Pts who received D+T-DXd had no DLTs and 1 had a Grade 1 troponin increase. D dose was delayed and T-DXd dose reduced for 2 (18%) pts each. Confirmed ORR was 4/4 (100%; only 4 pts had the opportunity to complete 2 on-treatment disease assessments) with all 4 remaining in response at data cutoff (median DoR not reached). Conclusions: D+P demonstrated a tolerable safety profile and response rate as expected for a 1L TNBC IO/taxane combination. D+T-DXd showed promising early safety and efficacy in 1L HER2-low–expressing TNBC; pt evaluation and enrollment for D+T-DXd are ongoing. D+T-DXd data will be updated and the impact of PD-L1 expression in both arms will be examined. Clinical trial information: NCT03742102 .

Emerging Therapeutic Drugs in Metastatic Triple-Negative Breast Cancer.

Metastatic triple-negative breast cancer (TNBC) is a heterogeneous disease with a poor prognosis and currently with few treatment options. Treatment of these patients is highly based on systemic chemotherapy. Some targeted drugs were recently approved for these patients: two poly(ADP-ribose) polymerase inhibitors in patients with germline BRCA1/2 mutations (olaparib and talazoparib), immune checkpoint inhibitors in association with chemotherapy if programmed death-ligand 1 positive (atezolizumab plus nabpaclitaxel and pembrolizumab plus chemotherapy [nabpaclitaxel, paclitaxel, and carboplatin plus gemcitabine]), and an antibody-drug conjugate sacituzumab-govitecan in heavily pretreated patients (at least 2 previous lines for the metastatic setting). Combinations using these and other targeted treatment options are under investigation in early and late clinical trials, and we will probably have some practice-changing results in the new future. Other targeted drugs explored in phase II and phase III clinical trials are PI3K/AKT pathway inhibitors and androgen receptor antagonists in patients with alterations in these signaling pathways. The definition of molecular subtypes has been essential for the development of these treatment strategies. Soon, the treatment of metastatic TNBC could be based on personalized medicine using molecular testing for targeted drugs instead of only systemic chemotherapy. The authors present a review of emerging treatment options in metastatic TNBC, focusing on targeted drugs, including the recent data published in 2020.

Abstract B11: mTOR pathway inhibition induces GPNMB expression and sensitizes breast cancer cells to an antibody-drug conjugate targeting GPNMB

Abstract The biggest challenge in the effective management of breast cancer is the limited duration of therapeutic benefit that is achieved with the current treatment options. Patients diagnosed with triple-negative breast cancer (TNBC), a type of breast tumor with worst prognoses, are currently treated with surgery, radiation and chemotherapy. Unfortunately, despite initial responses cancer cells become resistant to drugs and tumors relapse. We previously identified the cell surface protein GPNMB as a key mediator of breast cancer metastasis. Recently, an antibody-drug conjugate targeting GPNMB (Cdx-011) was developed that has been tested as single agent for the treatment of metastatic TNBC in a clinical trial. We have recently uncovered a novel response of TNBCs to therapeutic treatments: GPNMB expression is greatly elevated following treatment with mTOR pathway inhibitors (i.e., rapamycin, INK-128, AZD2014 and Torin-1) as well as conventional chemotherapy agents (doxorubicin, paclitaxel or cisplatin) and experimental treatments, i.e., MEK pathway inhibitors. Pharmacologically induced enhancement of GPNMB was also observed in ER+ cancers treated with antiestrogens (i.e., Fulvestrant). Interestingly, tumor cells that developed resistance to chemotherapy or antiestrogens exhibit higher levels of GPNMB. We found that therapy-induced GPNMB upregulation is mediated by the mobilization of the stress-induced MiTF/TFE family of transcription factors. In TNBC cells, mTOR inhibition promotes TFE3 nuclear translocation and GPNMB transcription. In ER+ cells, antiestrogens inactivate mTOR pathway causing TFE3 nucleus localization and GPNMB expression. We are currently conducting preclinical studies to investigate whether the upregulation of GPNMB caused by treatment with mTOR inhibitors could sensitize breast cancer cells to the activity of an antibody-drug conjugate targeting GPNMB (Cdx-011). Citation Format: Marco Biondini, April Rose, Matthew Annis, Cristiano Ferrario, Rosa Puertollano, Mark Basik, Peter Siegel. mTOR pathway inhibition induces GPNMB expression and sensitizes breast cancer cells to an antibody-drug conjugate targeting GPNMB [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr B11.

Pharmacoeconomic analysis of atezolizumab plus nab-paclitaxel in the treatment of the advanced or metastatic triple-negative breast cancer

Objective.To determine the pharmacoeconomical feasibility of using a combination of atezolizumab + nab-paclitaxel in the 1st line of therapy for locally advanced or metastatic triple negative breast cancer (TNBC) in adult PDL1 positive patients in the Russian healthcare system.Materials and methods.A decision analysis model was used followed by Markov modelling for the economic evaluation of the drugs in the treatment of metastatic TNBC. We used the «cost-effectiveness» analysis and the «impact on the budget» (BIA) analysis. Two therapeutic approaches were evaluated: the use of combined therapy with atezolizumab + nab-paclitaxel and monotherapy with nab-paclitaxel. The analysis included direct costs. Additionally, the obtained pharmacoeconomical indicators of the use of a combination of atezolizumab and nab-paclitaxel and other drugs for the treatment of locally advanced and metastatic breast cancer were compared.Results. The use of the estimated therapeutic approaches in the treatment of metastatic TNBC was characterized by the following costs: with a modelling horizon of 1 year, the cost of using atezolizumab in combination with nab-paclitaxel was 5,076,321 rubles per patient. The costs for the use of single agent nab-paclitaxel with was 60 % less than: — 2 020 038,78 RUB. At the same time, the effectiveness of therapy with a combination of atezolizumab and nab-paclitaxel clinically significantly exceeded that of nab-paclitaxel monotherapy: a 38 % reduction in the risk of death or progression, a 10-fold increase in the frequency of complete response to therapy (10 vs 1 %), and a 7-month increase in the median overall survival (25 vs 18 months). The economic evaluation of the combination of atezolizumab with nab-paclitaxel was carried out with the calculation of the incremental cost-effectiveness ratios (ICER) — the calculation of the additional cost for each additional year of life in comparison with standard therapy. Due to the fact that currently in Russia for patients with metastatic TNBC no similar performance modes of therapy ICER for the combination atezolizumab + nab-paclitaxel compared with the ICER for palbociclib in combination with fulvestrant (drugs, showed improved overall survival in clinical research and included in clinical guidelines for the treatment of diseases of the same class ICD-10 in locally advanced and metastatic breast cancer). The ICER for overall survival at the end of the first year of follow-up for atezolizumab + nab-paclitaxel and palbociclib + fulvestrant was 30.5 million rubles and 47.4 million rubles, respectively. For the combination of atezolizumab + nab-paclitaxel, ICER is lower than the similar ICER for the palbociclib + fulvestrant mode by 36 %. Analysis of trends in the weighted average cost of systemic pathogenetic treatment of breast cancer (breast cancer) shows the following: increased use of the combination of atezolizumab + nab-paclitaxel for the treatment of patients with metastatic TNBC doesn’t lead to a considerable growth in the cost of therapy in patients with breast cancer — providing therapy to 1400 patients that includes the entire target population of patients with TNBC and expression of PD-L1 in Russia changes in the costs of chemotherapy and immunotherapy of breast cancer will remain within 2.6 %.Conclusion. Pharmacoeconomic indicators of the use of atezolizumab in combination with nab-paclitaxel are more cost-effective in comparison with other expensive schemes for the treatment of breast cancer, and tumors of other localities that are actively used in current practice, which suggests the acceptability and feasibility of introducing and expanding the use of this therapeutic option in the target population.

Atezolizumab in the treatment of metastatic triple-negative breast cancer

ABSTRACT Introduction Triple-negative breast cancer (TNBC) accounts for approximately 10%-15% of all diagnosed breast cancers and is associated with an aggressive natural history and poor clinical outcomes. Immunotherapy using immune checkpoint inhibitors has emerged as an effective therapeutic option for TNBC. The results of the IMpassion130 trial have recently led to the approval of the combination of atezolizumab and nab-paclitaxel in the first-line treatment of patients with unresectable locally advanced or metastatic, PD-L1-positive TNBC. Areas covered This article summarizes the clinical development and ongoing research on atezolizumab in the treatment of metastatic TNBC. Results of atezolizumab monotherapy trials and data from combination studies with chemotherapy in the advanced setting are reviewed, with special focus on the design, methods, and key findings of the IMpassion130 trial. Expert opinion The approval of atezolizumab plus nab-paclitaxel represents an important advance in the treatment of metastatic TNBC. This combination has a favorable risk-benefit profile and is associated with clinically meaningful outcomes. However, further research is needed to identify better predictive biomarkers of response as well as novel immunotherapeutic strategies with atezolizumab and other anticancer drugs.

CONTESSA TRIO: A multinational, multicenter, phase (P) II study of tesetaxel (T) plus three different PD-(L)1 inhibitors in patients (Pts) with metastatic triple-negative breast cancer (TNBC) and tesetaxel monotherapy in elderly pts with HER2-metastatic breast cancer (MBC).

TPS1111 Background: Chemotherapy treatments with robust efficacy that preserve quality of life are needed. T is a novel, oral taxane that has potential advantages over currently available taxanes, including: oral administration with a low pill burden and once every 3 week (Q3W) dosing; no observed hypersensitivity reactions; preclinical evidence of central nervous system (CNS) penetration; and improved activity against chemotherapy-resistant tumors. More than 600 pts have been treated with T in clinical studies. T had robust monotherapy activity in a P2 study in 38 pts with HER2-, HR+ MBC, with a confirmed objective response rate (ORR) per RECIST 1.1 of 45%. Methods: CONTESSA TRIO is a 2-cohort, multinational, multicenter, P2 study. In Cohort 1, 90 pts (potential expansion to up to 150 pts) with metastatic TNBC who have not received prior chemotherapy for advanced disease will be randomized 1:1:1 to receive T at 27 mg/m2 Q3W plus either: (1) nivolumab at 360 mg Q3W; (2) pembrolizumab at 200 mg Q3W; or (3) atezolizumab at 1,200 mg Q3W. Nivolumab and pembrolizumab (PD-1 inhibitors) and atezolizumab (a PD-L1 inhibitor) are approved for the treatment of multiple types of cancer; atezolizumab, in combination with nab-paclitaxel, was recently approved in the US for the treatment of metastatic TNBC. The dual primary endpoints for Cohort 1 are ORR and progression-free survival (PFS). A sample size of 30 pts in each PD-(L)1 inhibitor treatment group has approximately 70% power to detect an ORR difference of ≥ 35% between the treatment group with the highest ORR and the treatment group with the lowest ORR. Secondary endpoints include duration of response (DoR) and overall survival (OS). Efficacy results for each of the 3 PD-(L)1 inhibitor combinations will be assessed for correlation with the results of each of the 3 approved PD-L1 diagnostic assays. CONTESSA TRIO is the first randomized clinical study to compare 3 approved PD-(L)1 inhibitors. In Cohort 2, 40 elderly pts (potential expansion to up to 60 pts) with HER2- MBC who have not received prior chemotherapy for advanced disease will receive T monotherapy at 27 mg/m2 Q3W. The primary endpoint for Cohort 2 is ORR. A sample size of 40 will allow the ORR to be estimated with a maximum standard error of < 8%. Secondary endpoints include PFS, DoR and OS. Pts with CNS metastases are eligible for both cohorts. The study was initiated in March 2019. Clinical trial information: NCT03952325 .

Abstract OT1-08-08: CONTESSA TRIO: A multinational, multicenter, phase 2 study of tesetaxel plus 3 different PD-(L)1 inhibitors in patients with metastatic triple-negative breast cancer (TNBC) and tesetaxel monotherapy in elderly patients with HER2- metastatic breast cancer (MBC)

Abstract Background: Chemotherapy treatments with robust efficacy that preserve quality of life are needed. Tesetaxel is a novel, oral taxane that has potential advantages over currently available taxanes, including: oral administration with a low pill burden and once every 3 week (Q3W) dosing; no observed hypersensitivity reactions; preclinical evidence of central nervous system (CNS) penetration; and improved activity against chemotherapy-resistant tumors. More than 600 patients have been treated with tesetaxel in clinical studies. Tesetaxel had robust monotherapy activity in a Phase 2 study in 38 patients with HER2-, HR+ MBC, with a confirmed objective response rate (ORR) per RECIST 1.1 of 45%. CONTESSA TRIO investigates tesetaxel plus 3 different PD-(L)1 inhibitors in patients with TNBC and tesetaxel monotherapy in elderly patients with HER2- MBC. Trial design: CONTESSA TRIO is a 2-cohort, multinational, multicenter, Phase 2 study. In Cohort 1, 90 patients (with potential expansion to up to 150 patients) with metastatic TNBC who have not received prior chemotherapy for advanced disease will be randomized 1:1:1 to receive tesetaxel at 27 mg/m2 Q3W plus either: (1) nivolumab at 360 mg Q3W; (2) pembrolizumab at 200 mg Q3W; or (3) atezolizumab at 1,200 mg Q3W. Nivolumab and pembrolizumab (PD-1 inhibitors) and atezolizumab (a PD-L1 inhibitor) are approved for the treatment of multiple types of cancer; atezolizumab, in combination with nab-paclitaxel, was recently approved in the U.S. for the treatment of metastatic TNBC. The dual primary endpoints for Cohort 1 are ORR and progression-free survival (PFS). A sample size of 30 patients in each PD-(L)1 inhibitor treatment group has approximately 70% power to detect an ORR difference of 35% or greater between the treatment group with the highest ORR and the treatment group with the lowest ORR. An increase in the sample size to 50 patients in each treatment group will increase the power to approximately 85%. Secondary endpoints include duration of response (DoR) and overall survival (OS). Efficacy results for each of the 3 PD-(L)1 inhibitor combinations will be assessed for correlation with the results of each of the 3 approved PD-L1 diagnostic assays. CONTESSA TRIO is the first randomized clinical study to compare 3 approved PD-(L)1 inhibitors. In Cohort 2, 40 elderly patients (with potential expansion to up to 60 patients) with HER2- MBC who have not received prior chemotherapy for advanced disease will receive tesetaxel monotherapy at 27 mg/m2 Q3W. The primary endpoint for Cohort 2 is ORR. A sample size of 40 will allow the ORR to be estimated with a maximum standard error of < 8%. An increase in the sample size to 60 patients will decrease the maximum standard error to < 6.5%. Secondary endpoints include PFS, DoR and OS. Patients with CNS metastases are eligible for both cohorts. The Study was initiated in March 2019. For further information on this trial, email joconnell@odonate.com or visit clinicaltrials.gov (NCT03952325). Citation Format: Sara Tolaney, Joanne Blum, Igor Bondarenko, Arlene Chan, Noshir DaCosta, Yin-Hsun Feng, Yann Izarzugaza, Sung-Bae Kim, Mei-Ching Liu, Maria Eva Peréz Lopéz, Mafalda Oliveira, Samuel Guan Wei Ow, Michel Pavic, Hope Rugo, Lee Schwartzberg, Agostina Stradella, Stew Kroll, Joseph O'Connell, Thomas Wei, Elizabeth Mittendorf. CONTESSA TRIO: A multinational, multicenter, phase 2 study of tesetaxel plus 3 different PD-(L)1 inhibitors in patients with metastatic triple-negative breast cancer (TNBC) and tesetaxel monotherapy in elderly patients with HER2- metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT1-08-08.

Triple-negative breast cancer: recent treatment advances.

Triple-negative breast cancer (TNBC) is a breast cancer subtype renowned for its capacity to affect younger women, metastasise early despite optimal adjuvant treatment and carry a poor prognosis. Neoadjuvant therapy has focused on combinations of systemic agents to optimise pathological complete response. Treatment algorithms now guide the management of patients with or without residual disease, but metastatic TNBC continues to harbour a poor prognosis. Innovative, multi-drug combination systemic therapies in the neoadjuvant and adjuvant settings have led to significant improvements in outcomes, particularly over the past decade. Recently published advances in the treatment of metastatic TNBC have shown impressive results with poly (ADP-ribose) polymerase (PARP) inhibitors and immunotherapy agents. Immunotherapy agents in combination with traditional systemic chemotherapy have been shown to alter the natural history of this devastating condition, particularly in patients whose tumours are positive for programmed cell death ligand 1 (PD-L1).

Abstract OT1-01-01: IMpassion131: A phase III study comparing 1L atezolizumab with paclitaxel vs placebo with paclitaxel in treatment-naive patients with inoperable locally advanced or metastatic triple negative breast cancer (TNBC)

Abstract Background: Chemotherapy (including paclitaxel) remains the predominant treatment for metastatic TNBC but clinical outcomes remain poor. Therefore, new therapeutic approaches are needed. Atezolizumab blocks the binding of PD-L1 to its receptors PD-1 and B7.1, thus restoring tumor-specific T cell immunity. TNBC is a rational target for atezolizumab therapy due to high PD-L1 expression on tumor-infiltrating immune cells (IC) and elevated T cell tumor infiltration. Furthermore, combining chemotherapy with atezolizumab is hypothesized to enhance anti-tumor immune response via neoantigen release. Atezolizumab alone and in combination with nab-paclitaxel has demonstrated promising clinical benefit in metastatic TNBC and was well tolerated, with no exacerbation of chemotherapy-associated adverse events. Atezolizumab in combination with nab-paclitaxel is being further investigated as 1L TNBC treatment in IMpassion130. IMpassion131 is a global, multi-center, randomized, double-blind, placebo-controlled study comparing the efficacy and safety of 1L atezolizumab + paclitaxel vs placebo + paclitaxel in patients with untreated, inoperable, locally advanced or metastatic TNBC. (NCT03125902) Methods: Eligibility criteria include patients with inoperable, locally advanced or metastatic TNBC, histologically confirmed; de novo or recurrent disease after early breast cancer treated with chemotherapy ≥ 12 months prior; eligible for taxane monotherapy; no prior chemotherapy or targeted systemic therapy for inoperable locally advanced or metastatic disease; ECOG PS 0-1 and measurable disease by RECIST v1.1. Exclusion criteria include known symptomatic CNS disease, prior immunotherapy and a history of autoimmune disease. Approximately 495 patients will be randomized 2:1 to receive atezolizumab (840 mg) or placebo (q2w; days 1 and 15 of 28-day cycle) plus paclitaxel (90 mg/m2; days 1, 8, 15 of 28-day cycle) until disease progression. Stratification factors are PD-L1 expression on tumor-infiltrating IC (IC0 < 1% vs IC1/2/3 ≥ 1% with VENTANA SP142 IHC assay), prior taxane therapy, presence of liver metastases and geographical region. The primary endpoint is progression-free survival (PFS) measured by RECIST v1.1. Key secondary endpoints include overall survival (OS), 12- and 18-month OS rates, 12-month PFS rate, objective response rate, duration of response, and safety. Tumor biopsies will be collected at baseline, on treatment and at disease progression to assess for biomarkers of treatment response and immune escape. Citation Format: Miles D, André F, Gligorov J, Verma S, Xu B, Cameron D, Barrios CH, Schneeweiss A, Easton V, Ghazi Y, O'Shaughnessy J. IMpassion131: A phase III study comparing 1L atezolizumab with paclitaxel vs placebo with paclitaxel in treatment-naive patients with inoperable locally advanced or metastatic triple negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT1-01-01.

Individual xenografts for personalized treatment of women with metastatic triple negative breast cancer

Aim: Triple negative breast cancer (TNBC) is the most severe subtype of breast cancer with poor prognosis even when treated at a localized stage. The treatment of metastatic TNBC is still challenging daily clinical practice, mainly because of the lack of targeted therapies. In the last years, a molecular sub-classification of TNBC has opened the way to personalized medicine for this type of severe cancer.