The Evolution of Triple-Negative Breast Cancer: From Biology to Novel Therapeutics

Triple-negative breast cancer (TNBC) is clinically defined as lacking expression of the estrogen receptor (ER), progesterone receptor (ER), and HER2. Historically, TNBC has been characterized by an aggressive natural history and worse disease-specific outcomes compared with other breast cancer subtypes. The advent of next-generation sequencing (NGS) has allowed for the dissection of TNBC into molecular subtypes (i.e., basal-like, claudin-low). Within TNBC, several subtypes have emerged as “immune-activated,” consistently illustrating better disease outcome. In addition, NGS has revealed a host of molecular features characteristic of TNBC, including high rates of TP53 mutations, PI3K and MEK pathway activation, and genetic similarities to serous ovarian cancers, including inactivation of the BRCA pathway. Identified genetic vulnerabilities of TNBC have led to promising therapeutic approaches, including DNA-damaging agents (i.e., platinum salts and PARP inhibitors), as well as immunotherapy. Platinum salts are routinely incorporated into the treatment of metastatic TNBC; however, best outcomes are observed among those with deficiencies in the BRCA pathway. Although the incorporation of platinum in the neoadjuvant care of patients with TNBC yields higher pathologic complete response (pCR) rates, the impact on longer-term outcome is less clear. The presence of immune infiltrate in TNBC has shown both a predictive and prognostic role. Checkpoint inhibitors, including PD-1 and PD-L1 inhibitors, are under investigation in the setting of metastatic TNBC and have shown responses in initial clinical trials. Finally, matching emerging therapeutic strategies to optimal subtype of TNBC is of utmost importance as we design future research strategies to improve patient outcome.

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Impact of the Addition of Carboplatin and/or Bevacizumab to Neoadjuvant Once-per-Week Paclitaxel Followed by Dose-Dense Doxorubicin and Cyclophosphamide on Pathologic Complete Response Rates in Stage II to III Triple-Negative Breast Cancer: CALGB 40603 (Alliance)

Journal of Clinical Oncology ◽

10.1200/jco.2014.57.0572 ◽

2015 ◽

Vol 33 (1) ◽

pp. 13-21 ◽

Cited By ~ 394

Author(s):

William M. Sikov ◽

Donald A. Berry ◽

Charles M. Perou ◽

Baljit Singh ◽

Constance T. Cirrincione ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Pathologic Complete Response ◽

Complete Response ◽

Stage Ii ◽

Open Label ◽

Grade 3 ◽

Dose Dense ◽

The Impact

Purpose One third of patients with triple-negative breast cancer (TNBC) achieve pathologic complete response (pCR) with standard neoadjuvant chemotherapy (NACT). CALGB 40603 (Alliance), a 2 × 2 factorial, open-label, randomized phase II trial, evaluated the impact of adding carboplatin and/or bevacizumab. Patients and Methods Patients (N = 443) with stage II to III TNBC received paclitaxel 80 mg/m2 once per week (wP) for 12 weeks, followed by doxorubicin plus cyclophosphamide once every 2 weeks (ddAC) for four cycles, and were randomly assigned to concurrent carboplatin (area under curve 6) once every 3 weeks for four cycles and/or bevacizumab 10 mg/kg once every 2 weeks for nine cycles. Effects of adding these agents on pCR breast (ypT0/is), pCR breast/axilla (ypT0/isN0), treatment delivery, and toxicities were analyzed. Results Patients assigned to either carboplatin or bevacizumab were less likely to complete wP and ddAC without skipped doses, dose modification, or early discontinuation resulting from toxicity. Grade ≥ 3 neutropenia and thrombocytopenia were more common with carboplatin, as were hypertension, infection, thromboembolic events, bleeding, and postoperative complications with bevacizumab. Employing one-sided P values, addition of either carboplatin (60% v 44%; P = .0018) or bevacizumab (59% v 48%; P = .0089) significantly increased pCR breast, whereas only carboplatin (54% v 41%; P = .0029) significantly raised pCR breast/axilla. More-than-additive interactions between the two agents could not be demonstrated. Conclusion In stage II to III TNBC, addition of either carboplatin or bevacizumab to NACT increased pCR rates, but whether this will improve relapse-free or overall survival is unknown. Given results from recently reported adjuvant trials, further investigation of bevacizumab in this setting is unlikely, but the role of carboplatin could be evaluated in definitive studies, ideally limited to biologically defined patient subsets most likely to benefit from this agent.

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Neoadjuvant Immune-Checkpoint Blockade in Triple-Negative Breast Cancer: Current Evidence and Literature-Based Meta-Analysis of Randomized Trials

Cancers ◽

10.3390/cancers12092497 ◽

2020 ◽

Vol 12 (9) ◽

pp. 2497

Author(s):

Daniele Marinelli ◽

Marco Mazzotta ◽

Laura Pizzuti ◽

Eriseld Krasniqi ◽

Teresa Gamucci ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Immune Checkpoint ◽

Randomized Trials ◽

Triple Negative ◽

Checkpoint Inhibitors ◽

Locally Advanced ◽

Pathologic Complete Response ◽

Current Evidence ◽

Metastatic Setting

Chemotherapy based on the sequential use of anthracyclines and taxanes has long represented the most efficacious approach in the management of early-stage, triple-negative breast cancer, whose aggressive behavior is widely renowned. This standard chemotherapy backbone was subsequently enriched by the use of carboplatin, based on its association with increased pathologic complete response and efficacy in the metastatic setting. Following the results from the IMpassion130 trial, the recent approval of the immunotherapic agent atezolizumab in combination with chemotherapy as first-line treatment for programmed-death ligand 1-positive, unresectable locally advanced, or metastatic triple-negative breast cancer increasingly fueled the flourishing of trials of immune-checkpoint inhibitors in the early setting. In this work, we review the most recent inherent literature in light of key methodological issues and provide a quantitative summary of the results from phase II–III randomized trials of immunotherapic agents combined with chemotherapy in the setting of interest. Hints regarding future directions are also discussed.

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Prospects of Immunotherapy for Triple-Negative Breast Cancer

Frontiers in Oncology ◽

10.3389/fonc.2021.797092 ◽

2022 ◽

Vol 11 ◽

Author(s):

Dan Qiu ◽

Guijuan Zhang ◽

Xianxin Yan ◽

Xinqin Xiao ◽

Xinyi Ma ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Immune Checkpoint ◽

Triple Negative ◽

Cytotoxic T Lymphocyte ◽

Checkpoint Inhibitors ◽

Death Receptor ◽

Cellular Immunotherapy ◽

T Cell Dysfunction ◽

The Impact

In the classification and typing of breast cancer, triple-negative breast cancer (TNBC) is one type of refractory breast cancer, while chemotherapy stays in the traditional treatment methods. However, the impact of chemotherapy is short-lived and may lead to recurrence due to incomplete killing of tumor cells. The occurrence, development, and relapse of breast cancer are relevant to T cell dysfunction, multiplied expression of related immune checkpoint molecules (ICIs) such as programmed death receptor 1 (PD-1), programmed cell death 1 ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) produce immunosuppressive effect. Immunotherapy (namely, immune checkpoint inhibitors, adoptive cellular immunotherapy, CAR-T immunotherapy and some potential treatments) provides new hope in TNBC. This review focuses on the new immune strategies of TNBC patients.

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Breast conservation after neoadjuvant chemotherapy for triple-negative breast cancer: Surgical results from an international randomized trial (BrighTNess).

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.514 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 514-514

Author(s):

Mehra Golshan ◽

Sibylle Loibl ◽

Jens Bodo Huober ◽

Joyce O'Shaughnessy ◽

Hope S. Rugo ◽

...

Keyword(s):

Breast Cancer ◽

Randomized Trial ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Brca Mutation ◽

Pathologic Complete Response ◽

Breast Conservation ◽

Complete Response ◽

Neoadjuvant Systemic Therapy ◽

The Impact

514 Background: Neoadjuvant systemic therapy (NST) increases the frequency of breast-conserving therapy (BCT) in stage II-III breast cancer, but there is little data on how often it converts patients (pts) from BCT-ineligible (BCT-I) to BCT-eligible (BCT-E) and on the impact of other factors on surgical choices. We collected surgical assessment and management data from an international randomized trial of NST in triple-negative breast cancer (TNBC). Methods: Women with operable TNBC were randomized to veliparib (V) with carboplatin (C) and paclitaxel (P), placebo with C and P or placebo with P followed by doxorubicin and cyclophosphamide. The surgeons assessed BCT candidacy by clinico-radiographic criteria before and after NST; surgical management was at surgeon and patient discretion. We assessed interactions between BCT eligibility pre- and post-NST, germline BRCA mutation ( gBRCA) status, continent of treatment and achievement of pathologic complete response(pCR) and percentage of pts who underwent BCT versus mastectomy. Results: Pre- and post-NST surgical assessments were available for 604 pts who underwent surgery. BCT rates are listed in the Table. The BCT rate was 68% among pts deemed BCT-E after NST. pCR rates were identical between BCT-E pts who chose BCT (55%) vs. mastectomy (53%). Of 141 pts deemed BCT-I at baseline, 75 (53%) converted to BCT-E but only 42 (56%) of these opted for BCT. pCR rates were 49% in BCT-E converts vs. 36% in those remained BCT-I. gBRCA pts (n = 84) were less likely to choose BCT even if they were BCT-E. Pts treated in North America (NA) were less likely to choose BCT (55% vs. 80% for Europe and Asia P<0.0001) even among non- gBRCA considered BCT-E post-NST (61% vs. 85% P<0.0001). Conclusions: This largest prospective analysis of the impact of NST in TNBC demonstrates a conversion rate from BCT-I to BCT-E of 53%. BCT rates were lower in pts with gBRCA; the much higher mastectomy rate among BCT-E pts in NA merits investigation. Clinical trial information: NCT02032277. [Table: see text]

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Comprehensive Transcriptome and Pathway Analyses Revealed Central Role for Fascin in Promoting Triple-Negative Breast Cancer Progression

Pharmaceuticals ◽

10.3390/ph14121228 ◽

2021 ◽

Vol 14 (12) ◽

pp. 1228

Author(s):

Rayanah Barnawi ◽

Samiyah Al-Khaldi ◽

Salma Majid ◽

Amal Qattan ◽

Tala Bakheet ◽

...

Keyword(s):

Breast Cancer ◽

Signaling Pathways ◽

Cancer Progression ◽

Triple Negative Breast Cancer ◽

Cellular Proliferation ◽

Triple Negative ◽

Checkpoint Inhibitors ◽

Breast Cancer Progression ◽

Differentially Expressed ◽

The Impact

Recent years have witnessed major progress in development of novel therapeutic agents such as chemotherapy, targeted therapy and immune checkpoint inhibitors for breast cancer. However, cancer-related death remains high especially in triple-negative breast cancer (TNBC) due limited therapeutic options. Development of targeted therapies for TNBC requires better understanding of biology and signaling networks that promote disease progression. Fascin, an actin bundling protein, was identified as a key regulator of many signaling pathways that contribute to breast cancer progression. Herein, fascin ShRNA was used to generate stable fascin knockdown (FSCN1KD) in the MDA-MB-231 TNBC cell line and then were subjected to comprehensive mRNA and miRNA transcriptome analysis. We identified 129 upregulated and 114 downregulated mRNA transcripts, while 14 miRNAs were differentially expressed in FSCN1KD. Ingenuity pathway analysis (IPA) was used to predict the impact of differentially expressed transcripts on signaling pathways and functional categories and to construct miRNA-mRNA regulatory networks in the context of FSCN1 knockdown. Compared to FSCN1KD, fascin-positive (FSCN1CON) breast cancer cells showed enrichment in genes promoting cellular proliferation, migration, survival, DNA replication and repair. Expression of FSCN1high (identified in BRCA dataset from TCGA) in conjunction with elevated expression of the top 10 upregulated or decreased expression of the top 10 downregulated genes (identified in our FSCN1CON vs. FSCN1KD) correlates with worst survival outcome. Taken together, these data confirmed fascin’s role in promoting TNBC progression, and identified a novel opportunity for therapeutic interventions via targeting those FSCN1-related transcripts.

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Clinical and genomic assessment of PD-L1 SP142 expression in triple-negative breast cancer

Breast Cancer Research and Treatment ◽

10.1007/s10549-021-06193-9 ◽

2021 ◽

Author(s):

Sung Gwe Ahn ◽

Seon-Kyu Kim ◽

Jonathan H. Shepherd ◽

Yoon Jin Cha ◽

Soong June Bae ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Checkpoint Inhibitors ◽

Pathologic Complete Response ◽

Gene Expression Signature ◽

Complete Response ◽

Gene Signature ◽

Expression Signature

Abstract Purpose The SP142 PD-L1 assay is a companion diagnostic for atezolizumab in metastatic triple-negative breast cancer (TNBC). We strove to understand the biological, genomic, and clinical characteristics associated with SP142 PD-L1 positivity in TNBC patients. Methods Using 149 TNBC formalin-fixed paraffin-embedded tumor samples, tissue microarray (TMA) and gene expression microarrays were performed in parallel. The VENTANA SP142 assay was used to identify PD-L1 expression from TMA slides. We next generated a gene signature reflective of SP142 status and evaluated signature distribution according to TNBCtype and PAM50 subtypes. A SP142 gene expression signature was identified and was biologically and clinically evaluated on the TNBCs of TCGA, other cohorts, and on other malignancies treated with immune checkpoint inhibitors (ICI). Results Using SP142, 28.9% of samples were PD-L1 protein positive. The SP142 PD-L1-positive TNBC had higher CD8+ T cell percentage, stromal tumor-infiltrating lymphocyte levels, and higher rate of the immunomodulatory TNBCtype compared to PD-L1-negative samples. The recurrence-free survival was prolonged in PD-L1-positive TNBC. The SP142-guided gene expression signature consisted of 94 immune-related genes. The SP142 signature was associated with a higher pathologic complete response rate and better survival in multiple TNBC cohorts. In the TNBC of TCGA, this signature was correlated with lymphocyte-infiltrating signature scores, but not with tumor mutational burden or total neoantigen count. In other malignancies treated with ICIs, the SP142 genomic signature was associated with improved response and survival. Conclusions We provide multi-faceted evidence that SP142 PDL1-positive TNBC have immuno-genomic features characterized as highly lymphocyte-infiltrated and a relatively favorable survival.

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Atorvastatin in Treating Patients With Stages IIb-III Triple Negative Breast Cancer Who Did Not Achieve a Pathologic Complete Response After Receiving Neoadjuvant Chemotherapy

Case Medical Research ◽

10.31525/ct1-nct03872388 ◽

2019 ◽

Author(s):

Keyword(s):

Breast Cancer ◽

Neoadjuvant Chemotherapy ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Pathologic Complete Response ◽

Complete Response

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Multi-Gene Testing Overview with a Clinical Perspective in Metastatic Triple-Negative Breast Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms22137154 ◽

2021 ◽

Vol 22 (13) ◽

pp. 7154

Author(s):

Martina Dameri ◽

Lorenzo Ferrando ◽

Gabriella Cirmena ◽

Claudio Vernieri ◽

Giancarlo Pruneri ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Checkpoint Inhibitors ◽

Gene Testing ◽

Repair Deficiency ◽

Targeted Treatments ◽

Recombination Repair ◽

Tumor Mutational Burden ◽

Next Generation Sequencing Ngs

Next-generation sequencing (NGS) is the technology of choice for the routine screening of tumor samples in clinical practice. In this setting, the targeted sequencing of a restricted number of clinically relevant genes represents the most practical option when looking for genetic variants associated with cancer, as well as for the choice of targeted treatments. In this review, we analyze available NGS platforms and clinical applications of multi-gene testing in breast cancer, with a focus on metastatic triple-negative breast cancer (mTNBC). We make an overview of the clinical utility of multi-gene testing in mTNBC, and then, as immunotherapy is emerging as a possible targeted therapy for mTNBC, we also briefly report on the results of the latest clinical trials involving immune checkpoint inhibitors (ICIs) and TNBC, where NGS could play a role for the potential predictive utility of homologous recombination repair deficiency (HRD) and tumor mutational burden (TMB).

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PITX2 DNA-Methylation: Predictive versus Prognostic Value for Anthracycline-Based Chemotherapy in Triple-Negative Breast Cancer Patients

Breast Care ◽

10.1159/000510468 ◽

2020 ◽

pp. 1-9

Author(s):

Rudolf Napieralski ◽

Gabriele Schricker ◽

Gert Auer ◽

Michaela Aubele ◽

Jonathan Perkins ◽

...

Keyword(s):

Breast Cancer ◽

Dna Methylation ◽

Cancer Patients ◽

Triple Negative Breast Cancer ◽

Predictive Value ◽

Untreated Patient ◽

Triple Negative ◽

Statistical Significance ◽

Breast Cancer Patients ◽

The Impact

Background: PITX2 DNA methylation has been shown to predict outcomes in high-risk breast cancer patients after anthracycline-based chemotherapy. To determine its prognostic versus predictive value, the impact of PITX2 DNA methylation on outcomes was studied in an untreated cohort vs. an anthracycline-treated triple-negative breast cancer (TNBC) cohort. Material and Methods: The percent DNA methylation ratio (PMR) of paired-like homeodomain transcription factor 2 (PITX2) was determined by a validated methylation-specific real-time PCR test. Patient samples of routinely collected archived formalin-fixed paraffin-embedded (FFPE) tissue and clinical data from 144 TNBC patients of 2 independent cohorts (i.e., 66 untreated patients and 78 patients treated with anthracycline-based chemotherapy) were analyzed. Results: The risk of 5- and 10-year overall survival (OS) increased continuously with rising PITX2 DNA methylation in the anthracycline-treated population, but it increased only slightly during 10-year follow-up time in the untreated patient population. PITX2 DNA methylation with a PMR cutoff of 2 did not show significance for poor vs. good outcomes (OS) in the untreated patient cohort (HR = 1.55; p = 0.259). In contrast, the PITX2 PMR cutoff of 2 identified patients with poor (PMR >2) vs. good (PMR ≤2) outcomes (OS) with statistical significance in the anthracycline-treated cohort (HR = 3.96; p = 0.011). The results in the subgroup of patients who did receive anthracyclines only (no taxanes) confirmed this finding (HR = 5.71; p = 0.014). Conclusion: In this hypothesis-generating study PITX2 DNA methylation demonstrated predominantly predictive value in anthracycline treatment in TNBC patients. The risk of poor outcome (OS) correlates with increasing PITX2 DNA methylation.

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