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Table of Contents

    Topic review

    Breast Cancer Treatments

    Subjects: Oncology
    View times: 38
    Submitted by: Francine Durocher

    Definition

    Breast cancer (BC) is the most frequent cancer diagnosed in women worldwide. This heterogeneous disease can be classified into four molecular subtypes (luminal A, luminal B, HER2 and triple-negative breast cancer (TNBC)) according to the expression of the estrogen receptor (ER) and the progesterone receptor (PR), and the overexpression of the human epidermal growth factor receptor 2 (HER2). Current BC treatments target these receptors (endocrine and anti-HER2 therapies) as a personalized treatment. Along with chemotherapy and radiotherapy, these therapies can have severe adverse effects and patients can develop resistance to these agents. Moreover, TNBC do not have standardized treatments. Hence it is essential to develop new treatments to target more effectively each BC subgroup. 

    1. Introduction

    Breast cancer (BC) is the most frequent cancer and the second cause of death by cancer in women worldwide. According to Cancer Statistics 2020, BC represents 30% of female cancers with 276,480 estimated new cases and more than 42,000 estimated deaths in 2020 [1].
    Invasive BC can be divided into four principal molecular subtypes by immunohistological technique based on the expression of the estrogen receptor (ER), the progesterone receptor (PR), and the human epidermal growth factor receptor 2 (HER2) [2]. Luminal A BC (ER+ and/or PR+, and HER2-) represents around 60% of BC and is associated with a good prognosis [3]. Luminal B BC (ER+ and/or PR+, and HER2+) represents 30% of BC and is associated with high ki67 (>14%), a proliferation marker, and a poor prognosis [4]. HER2 BC (ER-, PR-, and HER2+) represents 10% of BC and is also associated with a poor prognosis [5]. Lastly, triple-negative BC (TNBC) (ER-, PR-, and HER2-) represents 15–20% of BC and is associated with more aggressivity and worse prognosis compared to other BC molecular subtypes and often occurs in younger women [6]. Characteristics of BC by molecular subtypes are described in Figure 1.
    Figure 1. Characteristics of breast cancer molecular subtypes. ER: estrogen receptor; PR: progesterone receptor; HER2: human epidermal growth factor receptor 2; TNBC: triple-negative breast cancer. a. Frequency derived from Al-thoubaity et al. [7] and Hergueta-Redondo et al. [8]. b. Grade derived from Engstrom et al. [9]. c. Prognosis derived from Hennigs et al. [10] and Fragomeni et al. [11]. d. The 5–year survival rate derived from the latest survival statistics of SEER [12].
    The 5-year relative BC-specific survival rate of BC is encouraging with 90.3% for all subtypes and stages. However, for metastatic BC the 5-year relative cancer-specific survival rate is still low: 29% regardless of subtype and can drop to 12% for metastatic TNBC [12]. This clearly indicates that strategies of treatment for metastatic BC patients are not effective enough to ensure a good survival rate. Thus, it is crucial to find new solutions for the treatment of metastatic BC and especially TNBC.
    Treatment choice is based on the grade, stage, and BC molecular subtype to have the most personalized, safe, and efficient therapy. The grade describes the appearance of tumor cells compared to normal cells. It includes tubule differentiation, nuclear pleomorphism, and the mitotic count [13]. The stage is used to classify the extent of cancer in the body and is defined using the TNM system comprising tumor size, lymph node status, and the presence of metastases [14]. For non-metastatic BC, the strategic therapy involves removing the tumor by complete or breast-conserving surgery with preoperative (neoadjuvant) or postoperative (adjuvant) radiotherapy and systemic therapy including chemotherapy, and targeted therapy. Targeted therapy comprises endocrine therapy for hormone receptor-positive (HR+) BC and anti-HER2 therapy for HER2+ BC. Unfortunately, there is no available targeted therapy for the TNBC subtype. For metastatic BC the priority is to contain tumor spread as this type of BC remains incurable. The same systemic therapies are used to treat metastatic BC [15].
    Challenges in the treatment of BC including dealing with treatment resistance and recurrence. Indeed, 30% of early-stage BC have recurrent disease, mostly metastases [16]. Thus, it is crucial to develop new strategic therapies to treat each BC subgroup effectively.

    2. Common Treatments for All Breast Cancer Subtypes

    In addition to surgery, radiotherapy and chemotherapy are used routinely to treat all BC subtypes [17].

    2.1. Surgery

    The most standard breast surgery approaches are either total excision of the breast (mastectomy), usually followed by breast reconstruction, or breast-conserving surgery (lumpectomy). Lumpectomy entails the excision of the breast tumor with a margin of surrounding normal tissue. The recommended margins status is defined as “no ink on tumor”, meaning no remaining tumor cells at the tissue edge [18]. Studies show that total mastectomy and lumpectomy plus irradiation are equivalent regarding relapse-free and overall survival (OS) [19]. Contraindications for breast-conserving surgery include the presence of diffuse microcalcifications (suspicious or malignant-appearing), disease that cannot be incorporated by local excision with satisfactory cosmetic result, and ATM (ataxia-telangiesctasia mutated) mutation (biallelic inactivation) [18].

    2.2. Radiotherapy

    Radiation therapy has been used to treat cancer since Röngten discovered the X-ray in 1895 [20]. High-energy radiations are applied to the whole breast or a portion of the breast (after breast-conservative surgery), chest wall (after mastectomy), and regional lymph nodes [21]. Postmastectomy radiation to the chest wall in patients with positive lymph nodes is associated with decreased recurrence risk and BC mortality compared to patients with negative lymph nodes [22]. A radiation boost to the regional node radiation treatment can be incorporated after mastectomy for patients at higher risk for recurrence [23]. Radiotherapy can be administered concurrently with personalized therapy (anti-HER2 therapy or endocrine therapy).
    Radiation therapy is used to treat all BC subtypes, but its implication is more important for TNBC, as there is no personalized therapy for this subtype. It has been shown that radiotherapy benefits TNBC patients both after conserving surgery and mastectomy [24].

    2.3. Chemotherapy

    BC chemotherapy comprises several families of cytotoxic drugs, including alkylating agents, antimetabolites and tubulin inhibitors [25]. Cyclophosphamide is a nitrogen mustard alkylating agent causing breakage of the DNA strands [26]. The mechanism of action for anthracyclines (doxorubicin, daunorubicin, epirubicin, and idarubicin) includes DNA intercalation, thereby inhibiting macromolecular biosynthesis [27]. Taxanes, including docetaxel and paclitaxel, bind to microtubules and prevent their disassembly, leading to cell cycle arrest and apoptosis [28].
    Chemotherapy can be administered in the neoadjuvant or adjuvant setting and for metastatic BC treatment.

    3. Current Personalized Treatments for Breast Cancer: Strengths and Weaknesses

    The current strategies of treatment are principally based on the tumor progression and BC molecular subtypes in order to offer the most personalized treatment for BC patients. The algorithm of BC treatment is represented in Figure 2.
    Figure 2. Breast cancer treatment flow diagram. (A). Early-stage breast cancer. (B). Metastatic/advanced breast cancer. a Neoadjuvant chemotherapy for HR+ BC patients is not systematic. It is mainly administered to luminal B BC patients and/or elder BC patients. HR+: hormone receptors positive; HER2+: human epidermal growth factor receptor 2 positive; TNBC: triple-negative breast cancer; AIs: aromatase inhibitors; T-DM1: trastuzumab-emtansine.

    3.1. Endocrine Therapy

    Endocrine therapy is the main strategy to treat HR positive invasive BC. The purpose of this therapy is to target the ER directly (selective estrogen receptors modulators and degraders) or the estrogen synthesis (aromatase inhibitors) [29]. The most common types of endocrine therapy are selective estrogen receptor modulators (SERMs), selective modulators estrogen receptor degraders (SERDs), and aromatase inhibitors (AIs) [30]. Endocrine therapy mechanism of action and resistance are described in Figure 3.
    Figure 3. Endocrine therapy mechanisms of action and resistance. The left part of the figure shows the mechanism of endocrine therapy through aromatase inhibitors, tamoxifen, and fulvestrant. The right part of the figure describes the mechanisms of resistance to endocrine therapy through the epigenetic modifications, the increase of coactivators and cell cycle actors, and the activation of other signaling pathways. Estrogens can go through the plasma membrane by a. diffusion as they are small non-polar lipid soluble molecules; b. binding to membrane ER initiating the activation of Ras/Raf/MAPK and PI3K/Akt signaling pathways which are blocked by tamoxifen. 1: inhibition of ER dimerization; 2: blockage of nucleus access; 3: ER degradation. ER: estrogen receptor; AIB1: amplified in breast cancer 1; IGF-1R: insulin growth factor receptor 1; IGF: insulin growth factor; HER: human epidermal receptors; EGF: epidermal growth factor; HB-EGF: heparin-binding EGF-like growth factor; TGF-α: transforming growth factor alpha; MEK/MAPK: mitogen activated protein kinase; PI3K: phosphoinositide 3-kinase; mTOR: mammalian target of rapamycin; Me: methylation; Ac: acetylation.

    3.2. Anti-HER2 Therapy

    The overexpression of HER2 is associated with worse survival outcome compared to HR-positive/HER2-negative BC [31][32]. Hence, therapies targeting HER2 are essential to treat HER2-positive BC. The current anti-HER2 therapies comprise antibodies that target specific HER2 epitopes, tyrosine kinase inhibitors (TKIs) and, more recently, antibody-drug conjugates (ADCs) [33]. Anti-HER2 mechanisms of action and resistance are described in Figure 4.
    Figure 4. Anti-HER2 therapy mechanisms of action and resistance. The left part of the figure describes the mechanism of action of anti-HER2 therapy through anti-HER2 antibody (trastuzumab and pertuzumab), tyrosine kinase inhibitors (lapatinib and nerotinib), and the antibody-drug conjugate trastuzumab-emtansine (T-DM1). The right part of the figure describes the mechanism of resistance to anti-HER2 therapy through constitutive active p95HER2 fragment, activation of other signaling pathways, and rapid recycling of HER2-T-DM1. ADCC: antibody-dependent cellular cytotoxicity; HER2: human epidermal growth factor receptor 2; EGF: epidermal growth factor, HB-EGF: heparin-binding EGF-like growth factor; TGF-α: transforming growth factor alpha; T-DM1: trastuzumab-emtansine; IGF-1R: insulin growth factor receptor 1; IGF: insulin growth factor; HGF: hepatocyte growth factor; MEK/MAPK: mitogen activated protein kinase; PI3K: phosphoinositide 3-kinase; mTOR: mammalian target of rapamycin; PTEN: phosphatase and tensin homolog.

    3.3. PARP Inhibitors

    The prevalence of BRCA (Breast Cancer genes) mutations in TNBC patients is approximately 20% [34]. BRCA1 and BRCA2 are proteins involved in the DNA damage response to repair DNA lesions [35]. Mutations in BRCA 1/2 genes are associated with an increased risk of breast and ovarian cancers [36]. PARP (poly-(ADP-ribose) polymerase protein) proteins are also involved in the DNA damage response as they recruit DNA repair proteins, such as BRCA1 and BRCA2, to the damage site [37]. PARP inhibitors (PARPi) were developed to inhibit DNA repair in BRCA-mutated BC since cells defective in BRCA functions cannot repair DNA damage when PARP is inhibited [38]. The principal PARPis currently in clinical development are olaparib, talazoparib, veliparib, and rucaparib [39]. PARP inhibitors mechanisms of action and resistance are described in Figure 5.
    Figure 5. PARP inhibitors mechanisms of action and resistance. The left part of the figure describes the mechanism of PARP inhibitors in the context of BRCA mutated breast cancer. The right part of the figure describes the mechanism of resistance to PARP inhibitors through secondary intragenic mutations restoring BRCA proteins functions and the decrease of the recruitment of nucleases (MUS81 or MRE11) to protect the replication fork. PARP: poly-(ADP-ribose) polymerase protein; PARPi: PARP inhibitors; BRCA: breast cancer protein; MUS81: methyl methanesulfonate ultraviolet sensitive gene clone 81; MRE11: meiotic recombination 11.

    4. New Strategies and Challenges for Breast Cancer Treatment

    4.1. Emerging Therapies for HR-Positive Breast Cancer

    The major mechanisms of action of current endocrine therapy resistance occur via (1) the mTOR/PI3K/Akt signaling pathway and (2) the actors of the cell cycle progression CDK4/6. Therefore, emerging therapies for HR+ BC mainly target the actors of these pathways to bypass estrogen-independent cell survival [40]. The most recent completed clinical trials on emerging therapies for HR+ BC are presented in Table 1.
    Table 1. Most recent completed clinical trial on emerging therapies for HR-positive breast cancer.

    Targeted Therapy

    Drug Name

    Trial Number

    Patient Population

    Trial Arms

    Outcomes

    Pan-PI3K inhibitors

    Buparlisib

    BELLE-2

    Phase III

    NCT01610284

    [41]

    HR+/HER2-

    Postmenopausal

    Locally advanced or MBC

    Prior AI treatment

    Buparlisib + fulvestrant vs. placebo + fulvestrant

    PFS 6.9 months vs. 5.0 months (HR 0.78; p  =  0.00021)

    PFS 6.8 months vs. 4.0 months in PI3K mutated (HR 0.76; p  =  0.014)

    BELLE-3

    Phase III

    NCT01633060

    [42]

    HR+/HER2-

    Postmenopausal

    Locally advanced or MBC

    Prior endocrine therapy or mTOR inhibitors

    Buparlisib + fulvestrant vs. placebo + fulvestrant

    PFS 3.9 months vs. 1.8 months (HR 0.67; p  =  0.0003)

    BELLE-4

    Phase II/III

    NCT01572727

    [43]

    HER2-

    Locally advanced or MBC

    No prior chemotherapy

    Buparlisib + pacliatxel vs. placebo + paclitaxel

    PFS 8.0 months vs. 9.2 months (HR 1.18, 95% CI 0.82–1.68)

    PFS 9.1 months vs. 9.2 months in PI3K mutated (HR 1.17, 95% 0.63–2.17)

    Pictilisib

    FERGI

    Phase II

    NCT01437566

    [44]

    HR+/HER2-

    Postmenopausal

    Prior AI treatment

    Pictilisib + fulvestrant vs. placebo + fulvestrant

    PFS 6.6 months vs. 5.1 months (HR 0.74; p  =  0.096)

    PFS 6.5 months vs. 5.1 months in PI3K mutated (HR 0.74; p  =  0.268)

    PFS 5.8 months vs. 3.6 months in non-PI3K mutated (HR 0.72; p  =  0.23)

    PEGGY

    Phase II

    NCT01740336

    [45]

    HR+/HER2-

    Locally recurrent

    or MBC

    Pictilisib + paclitaxel vs. placebo + paclitaxel

    PFS 8.2 months vs. 7.8 months (HR 0.95; p  =  0.83)

    PFS 7.3 months vs. 5.8 months in PI3K mutated (HR 1.06; p  =  0.88)

    Isoform-specific inhibitors

    Alpelisib

    Phase Ib

    NCT01791478

    [46]

    HR+/HER2-

    Postmenopausal

    MBC

    Prior endocrine therapy

    Alpelisib + letrozole

    CBR 35% (44% in patients with PIK3CA mutated and 20% in PIK3CA wild-type tumors; 95% CI [17%; 56%])

    SOLAR-1

    Phase III

    NCT02437318

    [47]

    HR+/HER2-

    Advanced BC

    Prior endocrine therapy

    Alpelisib + fulvestrant vs. placebo + fulvestrant

    PFS 7.4 months vs. 5.6 months in non-PI3K mutated (HR 0.85, 95% CI 0.58–1.25)

    PFS 11.0 months vs. 5.7 months in PI3K mutated (HR 0.65; p  =  0.00065)

    NEO-ORB

    Phase II

    NCT01923168

    [48]

    HR+/HER2-

    Postmenopausal

    Early-stage BC

    Neoadjuvant setting

    Alpelisib + letrozole vs. placebo + letrozole

    ORR 43% vs. 45% (PIK3CA mutant), 63% vs. 61% (PIK3CA wildtype)

    pCR rates low in all groups

    Taselisib

    SANDPIPER

    Phase III

    NCT02340221

    [49]

    HR+/HER2-

    Postmenopausal

    Locally advanced or MBC

    PIK3CA-mutant

    Prior AI treatment

    Taselisib + fulvestrant vs. placebo + fulvestrant

    PFS 7.4 months vs. 5.4 months (HR 0.70; p  =  0.0037)

    LORELEI

    Phase II

    NCT02273973

    [50]

    HR+/HER2-

    Postmenopausal

    Early-stage BC

    Neoadjuvant setting

    Taselisib + letrozole vs. placebo + letrozole

    ORR 50% vs. 39.3% (OR 1.55; p  =  0.049)

    ORR 56.2% vs. 38% in PI3K mutated (OR 2.03; p  =  0.033)

    No significant difference in pCR

    mTOR inhibitors

    Everolimus

    BOLERO-2

    Phase III

    NCT00863655

    [51]

    HR+/HER2-

    Advanced BC

    Prior AI treatment

    Everolimus + exemestane

    vs. placebo + exemestane

    PFS 6.9 months vs. 2.8 months (HR 0.43; p < 0.001)

    TAMRAD

    Phase II

    NCT01298713

    [52]

    HR+/HER2-

    Postmenopausal

    MBC

    Prior AI treatment

    Everolimus + tamoxifen vs. tamoxifen alone

    CBR 61% vs. 42%

    TTP 8.6 months vs. 4.5 months (HR 0.54)

    PrE0102

    Phase II

    NCT01797120

    [53]

    HR+/HER2-

    Postmenopausal

    MBC

    Prior AI treatment

    Everolimus + fulvestrant

    vs. placebo + fulvestrant

    PFS 10.3 months vs. 5.1 months (HR 0.61; p = 0.02)

    CBR 63.6% vs. 41.5% (p = 0.01)

    Akt inhibitors

    Capivasertib

    FAKTION

    Phase II

    NCT01992952

    [54]

    HR+/HER2-

    Postmenopausal

    Locally advanced or MBC

    Prior AI treatment

    Capivasertib + fulvestrant vs. placebo + fulvestrant

    PFS 10.3 months vs. 4.8 months (HR 0.57; p  =  0.0035)

    Phase I

    NCT01226316

    [55]

    ER+

    AKT1E17K-mutant

    MBC

    Prior endocrine treatment

    Capivasertib + fulvestrant vs. Capivasertib alone

    CBR 50% vs. 47%

    ORR 6% (fulvestrant-pretreated) and 20% (fulvestrant-naïve) vs. 20%

    CDK4/6 inhibitors

    Palcociclib

    PALOMA-1

    Phase II

    NCT00721409

    [56]

    HR+/HER2-

    Postmenopausal

    Advanced BC

    No prior systemic treatment

    Palbocilib + letrozole vs. letrozole alone

    PFS 20.2 months vs. 10.2 months (HR 0.488; p = 0.0004)

    PFS 26.1 months vs. 5.7 months (HR 0.299; p < 0.0001) in non-Cyclin D1 amplified

    PFS 18.1 months vs. 11.1 months (HR 0.508; p = 0.0046) in Cyclin D1 amplified

    PALOMA-2

    Phase III

    NCT01740427

    [57]

    HR+/HER2-

    Postmenopausal

    Advanced BC

    No prior systemic treatment

    Palbocilib + letrozole vs. placebo + letrozole

    PFS 24.8 months vs. 14.5 months (HR 0.58; p < 0.001)

    PALOMA-3

    Phase III

    NCT01942135

    [58]

    HR+/HER2-

    MBC

    Prior endocrine therapy

    Palbociclib + fulvestrant

    vs. placebo + fulvestrant

    PFS 9.5 months vs. 4.6 months (HR 0.46; p < 0.0001)

    Ribociclib

    MONALEESA-2

    Phase III

    NCT01958021

    [59]

    HR+/HER2-

    Postmenopausal

    Advanced or MBC

    Ribociclib + letrozole vs. placebo + letrozole

    PFS 25.3 months vs. 16.0 months (HR 0.568; p < 0.0001)

    MONALEESA-3

    Phase III

    NCT02422615

    [60]

    HR+/HER2-

    Advanced BC

    No prior treatment or prior endocrine therapy

    Ribociclib + fulvestrant vs. placebo + fulvestrant

    PFS 20.5 months vs. 12.8 months (HR 0.593; p < 0.001)

    Abemaciclib

    MONARCH-2

    Phase III

    NCT02107703

    [61]

    HR+/HER2-

    Advanced or MBC

    Prior endocrine treatment

    Abemaciclib + fulvestrant vs. fulvestrant alone

    PFS 16.4 months vs. 9.3 months (HR 0.553; p < 0.001)

    MONARCH-3

    Phase III

    NCT02246621

    [62]

    HR+/HER2-

    Advanced or MBC

    Prior endocrine treatment

    Abemaciclib + anastrozole or letrozole vs. placebo + anastrozole or letrozole

    PFS 28.18 months vs. 14.76 months (HR 0.546; p < 0.0001)

    HR+: hormone receptors positive; HER2-: human epidermal growth factor receptor 2 negative; MBC: metastatic breast cancer; BC: breast cancer; PFS: progression free survival; CBR: clinical benefit rate; ORR: objective response rate; pCR: pathologic complete response; HR: hazard ratio.

    4.2. New Strategic Therapies for HER2-Positive Breast Cancer

    HER2+ BC is currently treated with specific HER2 targeting antibodies or tyrosine kinase inhibitors (TKIs), and more recently, with TDM-1, an antibody-drug conjugate. These treatments have greatly improved HER2+ BC survival. However, 25% of HER2+ BC patients will still develop resistance to anti-HER2 treatment. Hence, new therapeutic strategies are emerging, such as new antibodies targeting HER2, new TKIs, vaccines, and PI3K/mTOR and CDK4/6 inhibitors [63]. The most recent completed clinical trials on new strategies for HER2+ BC treatment are gathered in Table 2.
    Table 2. Most recent completed clinical trials on emerging therapies for HER2+ breast cancer.

    Targeted Therapy

    Drug Name

    Trial Number

    Patient Population

    Trial Arms

    Outcomes

    Antibodies drug conjugate (ADC)

    Trastuzumab-deruxtcan

    (DS-8201a)

    DESTINY-Breast01

    Phase II

    NCT03248492

    [64]

    HER2+

    MBC

    Prior trastuzumab-emtansine treatment

    Trastuzumab-deruxtcan monotherapy

    PFS 16.4 months

    Trastuzumab-duocarmycin (SYD985)

    Phase I dose-escalation and dose-expansion

    NCT02277717

    [65]

    HER2+

    Locally advanced or metastatic solid tumors

    Trastuzumab-duocarmycin monotherapy

    ORR 33%

    Modified antibodies

    Margetuxumab (MGAH22)

    SOPHIA

    Phase III

    NCT02492711

    [66]

    HER2+

    Advanced or MBC

    Prior anti-HER2 therapies

    Margetuximab + chemotherapy vs. trastuzumab + chemotherapy

    PFS 5.8 months vs. 4.9 months (HR 0.76; p = 0.03)

    OS 21.6 months vs. 19.8 months (HR 0.89; p = 0.33)

    ORR 25% vs. 14% (p < 0.001)

    Tyrosine kinase inhibitors

    Tucatinib

    HER2CLIMB

    Phase II

    NCT02614794

    [67]

    HER2+

    Locally advanced or MBC

    Prior anti-HER2 therapies

    Tucatinib + trastuzumab and capecitabine vs. placebo + trastuzumab and capecitabine

    PFS 33.1% (7.8 months) vs. 12.3% (5.6 months) (HR 0.54; p < 0.001)

    PFS 24.9% vs. 0% (HR 0.48; p < 0.001) in brain metastases patients

    OS 44.9% vs. 26.6% (HR 0.66; p = 0.005)

    Poziotinib

    NOV120101-203

    Phase II

    NCT02418689

    [68]

    HER2+

    MBC

    Prior chemotherapy and trastuzumab

    Poziotinib monotherapy

    PFS 4.04 months

    HER2-derived peptide vaccine

    E75 (NeuVax)

    Phase I/II

    NCT00841399

    NCT00854789

    [69]

    HER2+

    Node-positive or high-risk node-negative BC

    HLA2/3+

    E75 vaccination vs. non-vaccination

    DFS 89.7% vs. 80.2% (p = 0.008)

    DFS 94.6% in optimal dosed patients (p = 0.005 vs. non-vaccination)

    GP2

    Phase II

    NCT00524277

    [70]

    HER2 (IHC 1-3+)

    Disease free

    Node-positive or high-risk node-negative BC

    HLA2+

    GP2 + GM-CSF vs. GM-CSF alone

    DFS 94% vs. 85% (p = 0.17)

    DFS 100% vs. 89% in HER2-IHC3+ (p = 0.08)

    AE37

    Phase II

    NCT00524277

    [71]

    HER2 (IHC 1-3+)

    Node-positive or high-risk node-negative BC

    AE37 + GM-CSF vs. GM-CSF alone

    DFS 80.8% vs. 79.5% (p = 0.70)

    DFS 77.2% vs. 65.7% (p = 0.21) HER2-low

    DFS 77.7% vs. 49.0% (p = 0.12) TNBC

    PI3K inhibitors

    Alpelisib

    Phase I

    NCT02167854

    [72]

    HER2+

    MBC with a PIK3CA mutation Prior ado-trastuzumab emtansine and pertuzumab

    Alpelisib + Trastuzumab + LJM716

    Toxicities limited drug delivery 72% for alpelisib 83% for LJM716

    Phase I

    NCT02038010

    [73]

    HER2+

    MBC

    Prior trastuzumab-based therapy

    Alpelisib + T-DM1

    PFS 8.1 months

    ORR 43%

    CBR 71% and 60% in prior T-DM1 patients

    Copanlisib

    PantHER

    Phase Ib

    NCT02705859

    [74]

    HER2+

    Advanced BC

    Prior anti-HER2 therapies

    Copanlisib + trastuzumab

    Stable disease 50%

    mTOR inhibitors

    Everolimus

    BOLERO-1

    Phase III

    NCT00876395

    [75]

    HER2+

    Locally advanced BC

    No prior treatment

    Everolimus + trastuzumab vs. placebo + trastuzumab

    PFS 14.95 months vs. 14.49 months (HR 0.89; p = 0.1166)

    PFS 20.27 months vs. 13.03 months (HR 0.66; p = 0.0049)

    BOLERO-3

    Phase III

    NCT01007942

    [76]

    HER2+

    Advanced BC

    Trastuzumab-resistant

    Prior taxane therapy

    Everolimus + trastuzumab and vinorelbine vs. placebo + trastuzumab and vinorelbine

    PFS 7.00 months vs. 5.78 months (HR 0.78; p = 0.0067)

    CDK4/6 inhibitors

    Palbociclib

    SOLTI-1303 PATRICIA

    Phase II

    NCT02448420

    [77]

    HER2+

    ER+ or ER-

    MBC

    Prior standard therapy including trastuzumab

    Palbociclib + trastuzumab

    PFS 10.6 months (luminal) vs. 4.2 months (non-luminal) (HR 0.40; p = 0.003)

    Ribociclib

    Phase Ib/II

    NCT02657343

    [78]

    HER2+

    Advanced BC

    Prior treatment with trastuzumab, pertuzumab, and trastuzumab emtansine

    Ribociclib + trastuzumab

    PFS 1.33 months

    No dose-limiting toxicities

    Abemaciclib

    MonarcHER

    Phase II

    NCT02675231

    [79]

    HER2+

    Locally advanced or MBC

    Prior anti-HER2 therapies

    Abemaciclib + trastuzumab and fulvestrant (A) vs. abemaciclib + trastuzumab (B) vs. standard-of-care chemotherapy + trastuzumab (C)

    PFS 8.3 months (A) vs. 5.7 months (C) (HR 0.67; p = 0.051)

    PFS 5.7 months (B) vs. 5.7 months (C) (HR 0.97; p = 0.77)

    HER2+: human epidermal growth factor receptor 2 positive; ER+: estrogen receptor positive; HLA2/3: human leucocyte antigen 2/3; MBC: metastatic breast cancer; BC: breast cancer; PFS: progression free survival; CBR: clinical benefit rate; ORR: objective response rate; DFS: disease-free survival OS: overall survival GM-CSF: granulocyte macrophage colony-stimulated factor; HR: hazard ratio.

    4.3. Emerging Therapies for Triple Negative Breast Cancer (TNBC)

    TNBC is the most aggressive BC subtype. The fact that TNBC lacks ER and PR expression and does not overexpress HER2, combined with its high heterogeneity, has contributed to the difficulties in developing efficient therapies [80]. Thus, multiple strategic therapies have been developed to treat all TNBC subtypes. These include conjugated antibodies, targeted therapy, and immunotherapy. An overview of the most recent and completed clinical trials on emerging therapies for TNBC is presented in Table 3.
    Table 3. Most recent completed clinical trials on emerging therapies for TNBC.

    Targeted Therapy

    Drug Name

    Trial Number

    Patient Population

    Trial Arms

    Outcomes

    Antibodies Drug Conjugate

    Sacituzumab govitecan

    ASCENT

    Phase III

    NCT02574455

    [81]

    TNBC

    MBC

    Prior standard treatment

    Sacituzumab govitecan vs. single-agent chemotherapy

    PFS 5.6 months vs. 1.7 months (HR 0.41; p < 0.001)

    PFS 12.1 months vs. 6.7 months (HR 0.48; p < 0.001)

    VEGF inhibitors

    Bevacizumab

    BEATRICE

    Phase III

    NCT00528567

    [82]

    Early TNBC

    Surgery

    Bevacizumab + chemotherapy vs. chemotherapy alone

    IDFS 80% vs. 77%

    OS 88% vs. 88%

    CALGB 40603

    Phase II

    NCT00861705

    [83]

    TNBC

    Stage II to III

    Bevacizumab + chemotherapy vs. chemotherapy alone or Carboplatin + chemotherapy vs. chemotherapy alone

    pCR 59% vs. 48% (p = 0.0089) (Bevacizumab)

    pCR 60% vs. 44% (p = 0.0018) (Carboplatin)

    EGFR inhibitors

    Cetuximab

    TBCRC 001

    Phase II

    NCT00232505

    [84]

    TNBC

    MBC

    Cetuximab + carboplatin

    Response < 20%

    TTP 2.1 months

    Phase II

    NCT00463788

    [85]

    TNBC

    MBC

    Prior chemotherapy treatment

    Cetuximab + cisplatin vs. cisplatin alone

    ORR 20% vs. 10% (p = 0.11)

    PFS 3.7 months vs. 1.7 months (HR 0.67; p = 0.032)

    OS 12.9 months vs. 9.4 months (HR 0.82; p = 0.31)

    mTORC1 inhibitors

    Everolimus

    Phase II

    NCT00930930

    [86]

    TNBC

    Stage II or III

    Neoadjuvant treatment

    Everolimus + cisplatin and paclitaxel vs. placebo + cisplatin and paclitaxel

    pCR 36% vs. 49%

    Akt inhibitors

    Ipatasertib

    LOTUS

    Phase II

    NCT02162719

    [87]

    TNBC

    Locally advanced or MBC

    No prior sytemic therapy

    Ipatasertib + paclitaxel vs. placebo + paclitaxel

    PFS 6.2 months vs. 4.9 months (HR 0.60; p = 0.037)

    PFS 6.2 months vs. 3.7 moths (HR 0.58; p = 0.18) in PTEN-low patients

    FAIRLANE

    Phase II

    NCT02301988

    [88]

    Early TNBC

    Neoadjuvant treatment

    Ipatasertib + paclitaxel vs. placebo + paclitaxel

    pCR 17% vs. 13%

    pCR 16% vs. 13% PTEN-low patients

    pCR 18% vs. 12% PIK3CA/AKT1/PTEN-altered patients

    Capivasertib

    PAKT

    Phase II

    NCT02423603

    [89]

    TNBC

    MBC

    No prior chemotherapy treatment

    Capivasertib + paclitaxel vs. placebo + paclitaxel

    PFS 5.9 months vs. 12.6 months (HR 0.61; p = 0.04)

    Androgen receptor inhibitors

    Bicalutamide

    Phase II

    NCT00468715

    [90]

    HR-

    AR+ or AR-

    MBC

    Bicalutamide monotherapy

    CBR 19%

    PFS 12 weeks

    Enzalutamide

    Phase II

    NCT01889238

    [91]

    TNBC

    AR+

    Locally advanced or MBC

    Enzalutamide monotherapy

    CBR 25%

    OS 12.7 months

    CYP17 inhibitors

    Abiraterone acetate

    UCBG 12-1

    Phase II

    NCT01842321

    [92]

    TNBC

    AR+

    Locally advanced or MBC

    Centrally reviewed

    Prior chemotherapy

    Abiraterone acetate + prednisone

    CBR 20%

    ORR 6.7%

    PFS 2.8 months

    Anti-PDL1 antibodies

    Atezolizumab

    Impassion 130

    Phase III

    NCT02425891

    [93]

    TNBC

    Locally advanced or MBC

    No prior treatment

    Atezolizumab + nab-paclitaxel vs. placebo + nab-paclitaxel

    OS 21.0 months vs. 18.7 months (HR 0.86; p = 0.078)

    OS 25.0 months vs. 18.0 months (HR 0.71, 95% CI 0.54–0.94)) in PDL-1+ patients

    Impassion 031

    Phase III

    NCT03197935

    [94]

    TNBC

    Stage II to III

    No prior treatment

    Atezolizumab + chemotherapy vs. placebo + chemotherapy

    pCR 95% vs. 69% p = 0.0044

    Durvalumab

    GeparNuevo

    Phase II

    NCT02685059

    [95]

    TNBC

    MBC

    Stromal tumor-infiltrating lymphocyte (sTILs)

    Durvalumab vs. placebo

    pCR 53.4% vs. 44.2%

    pCR 61.0% vs. 41.4% in window cohort

    SAFIRO BREAST-IMMUNO

    Phase II

    NCT02299999

    [96]

    HER2-

    MBC

    Prior chemotherapy

    Durvalumab vs. maintenance chemotherapy

    HR of death 0.37 for PDL-1+ patients

    HR of death 0.49 for PDL-1- patients

    Phase I

    NCT02484404

    [97]

    Recurrent women’s cancers including TNBC

    Durvalumab + cediranib + olaparib

    Partial response 44%

    CBR 67%

    Avelumab

    JAVELIN

    Phase Ib

    NCT01772004

    [98]

    MBC

    Prior standard-of-care therapy

    Avelumab monotherapy

    ORR 3.0% overall

    ORR 5.2% in TNBC

    ORR 16.7% in PDL-1+ vs. 1.6% in PDL-1- overall

    ORR 22.2.% in PDL-1+ vs. 2.6% in PDL-1- in TNBC

    Anti-PD1 antibodies

    Pembrolizumab

    KEYNOTE-086

    Phase II

    NCT02447003

    [99]

    TNBC

    MBC

    Prior or no prior systemic therapy

    Pembrolizumab monotherapy

    Previously treated patients:

    ORR 5.3% overall

    ORR 5.7% PDL-1+ patients

    PFS 2.0 months

    OS 9.0 months

    Non-previously pretreated:

    ORR 21.4%

    PFS 2.1 months

    OS 18.0 months

    KEYNOTE-119

    Phase III

    NCT02555657

    [100]

    TNBC

    MBC

    Prior systemic therapy

    Pembrolizumab vs. chemotherapy

    OS 12.7 months vs. 11.6 months (HR 0.78; p = 0.057) in PDL1+ patients

    OS 9.9 months vs. 10.8 months (HR 0.97, 95% CI 0.81–1.15)

    KEYNOTE-355

    Phase III

    NCT02819518

    [101]

    TNBC

    MBC

    No prior systemic therapy

    Pembrolizumab + chemotherapy vs. placebo + chemotherapy

    PFS 9.7 months vs. 5.6 months (HR 0.65; p = 0.0012) in PDL-1+ patients

    PFS 7.6 months vs. 5.6 months (HR 0.74; p = 0.0014)

    KEYNOTE-522

    Phase III

    NCT03036488

    [102]

    Early TNBC

    Stage II to III

    No prior treatment

    Pembrolizumab + paclitaxel and carboplatin vs. placebo + paclitaxel and carboplatin

    pCR 64.8% vs. 51.2 % (p < 0.001)

    Anti-CDL4 antibodies

    Tremelimumab

    Phase I

    [103]

    Incurable MBC

    Tremelimumab + radiotherapy

    OS 50.8 months

    Vaccines

    PPV

    Phase II

    UMIN000001844

    [104]

    TNBC

    MBC

    Prior systemic therapy

    PPV vaccine

    PFS 7.5 months

    OS 11.1 months

    STn-KLH

    Phase III

    NCT00003638

    [105]

    MBC

    Prior chemotherapy

    Partial or complete response

    STn-KLH vaccine vs. non-vaccine

    TTP 3.4 months vs. 3.0 months

    TNBC: triple negative breast cancer; HER2: human epidermal growth factor receptor; HR: hormonal receptor; MBC: metastatic breast cancer; BC: breast cancer; AR: androgen receptor; PPV: personalized peptide vaccine; PFS: progression free survival; CBR: clinical benefit rate; ORR: objective response rate; IDFS: invasive disease-free survival; OS: overall survival; TTP: time to progression; pCR: pathologic complete response; HR: hazard ratio.

    The entry is from 10.3390/jpm11080808

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