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Please note this is a comparison between Version 1 by Francine Durocher and Version 2 by Peter Tang.
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.
- breast cancer
- personalized therapies
- molecular subtypes
- breast cancer treatment
- luminal
- HER2
- TNBC
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][12] and Hergueta-Redondo et al. [8][13]. b. Grade derived from Engstrom et al. [9][14]. c. Prognosis derived from Hennigs et al. [10][15] and Fragomeni et al. [11][16]. d. The 5–year survival rate derived from the latest survival statistics of SEER [12][7].
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][7]. 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][8]. 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][9]. 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][10].
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][11]. Thus, it is crucial to develop new strategic therapies to treat each BC subgroup effectively.
2. Common Treatments for All Breast Cancer Subtypes
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][22]. 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][23]. 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][25]. A radiation boost to the regional node radiation treatment can be incorporated after mastectomy for patients at higher risk for recurrence [23][26]. 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][39].
2.3. Chemotherapy
BC chemotherapy comprises several families of cytotoxic drugs, including alkylating agents, antimetabolites and tubulin inhibitors [25][40]. Cyclophosphamide is a nitrogen mustard alkylating agent causing breakage of the DNA strands [26][41]. The mechanism of action for anthracyclines (doxorubicin, daunorubicin, epirubicin, and idarubicin) includes DNA intercalation, thereby inhibiting macromolecular biosynthesis [27][42]. Taxanes, including docetaxel and paclitaxel, bind to microtubules and prevent their disassembly, leading to cell cycle arrest and apoptosis [28][43].
Chemotherapy can be administered in the neoadjuvant or adjuvant setting and for metastatic BC treatment.
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.
3. Current Personalized Treatments for Breast Cancer: Strengths and Weaknesses
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][67]. The most common types of endocrine therapy are selective estrogen receptor modulators (SERMs), selective modulators estrogen receptor degraders (SERDs), and aromatase inhibitors (AIs) [30][68]. 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][128,129]. 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][130]. 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][193]. BRCA1 and BRCA2 are proteins involved in the DNA damage response to repair DNA lesions [35][194]. Mutations in BRCA 1/2 genes are associated with an increased risk of breast and ovarian cancers [36][195]. 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][196]. 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][197]. The principal PARPis currently in clinical development are olaparib, talazoparib, veliparib, and rucaparib [39][198]. 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][229]. The most recent completed clinical trials on emerging therapies for HR+ BC are presented in Table 1.
Most recent completed clinical trials on emerging therapies for HER2+ breast cancer.
Table 1. Most recent completed clinical trial on emerging therapies for HR-positive breast cancer.
Targeted Therapy | Drug Name |
|---|
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][263]. The most recent completed clinical trials on new strategies for HER2+ BC treatment are gathered in Table 2.
Table 2.
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][308]. 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.
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.