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Somatic Mutations in HER2 and Implications for Current Treatment Paradigms in HER2-Positive Breast Cancer

Somatic Mutations in HER2 and Implications for Current Treatment Paradigms in HER2-Positive... Hindawi Journal of Oncology Volume 2020, Article ID 6375956, 13 pages https://doi.org/10.1155/2020/6375956 Review Article Somatic Mutations in HER2 and Implications for Current Treatment Paradigms in HER2-Positive Breast Cancer Maria Gaibar , Laura Beltra´n , Alicia Romero-Lorca , Ana Ferna´ndez-Santander , and Apolonia Novillo Faculty of Biomedical Sciences and Health, Universidad Europea de Madrid, C/Tajo, S/N, 28670 Villaviciosa de Odo´n, Madrid, Spain Correspondence should be addressed to Apolonia Novillo; apolonia.novillo@universidadeuropea.es Received 28 October 2019; Revised 28 January 2020; Accepted 6 February 2020; Published 7 March 2020 Guest Editor: Cigdem Selli Copyright © 2020 Maria Gaibar et al. *is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In one of every four or five cases of breast cancer, the human epidermal growth factor receptor-2 (HER2) gene is overexpressed. *ese carcinomas are known as HER2-positive. HER2 overexpression is linked to an aggressive phenotype and a lower rate of disease-free and overall survival. Drugs such as trastuzumab, pertuzumab, lapatinib, neratinib, and the more recent afatinib target the deregulation of HER2 expression. Some authors have attributed somatic mutations in HER2, a role in resistance to anti-HER2 therapy as differential regulation of HER2 has been observed among patients. Recently, studies in metastatic ER + tumors suggest that some HER2 mutations emerge as a mechanism of acquired resistance to endocrine therapy. In an effort to identify possible biomarkers of the efficacy of anti-HER2 therapy, we here review the known single-nucleotide polymorphisms (SNPs) of the HER2 gene found in HER2-positive breast cancer patients and their relationship with clinical outcomes. Information was recompiled on 11 somatic HER2 SNPs. Seven polymorphisms are located in the tyrosine kinase domain region of the gene contrasting with the low number of mutations found in extracellular and transmembrane areas. HER2-positive patients carrying S310F, S310Y, R678Q, D769H, or I767M mutations seem good candidates for anti-HER2 therapy as they show favorable outcomes and a good response to current pharmacological treatments. Carrying the L755S or D769Y mutation could also confer benefits when receiving neratinib or afatinib. By contrast, patients with mutations L755S, V842I, K753I, or D769Y do not seem to benefit from tras- tuzumab. Resistance to lapatinib has been reported in patients with L755S, V842I, and K753I. *ese data suggest that exploring HER2 SNPs in each patient could help individualize anti-HER2 therapies. Advances in our understanding of the genetics of the HER2 gene and its relations with the efficacy of anti-HER2 treatments are needed to improve the outcomes of patients with this aggressive breast cancer. therapy. About 20–25% of all breast cancers overexpress 1. Introduction human epidermal growth factor receptor-2 (HER2) and are Breast cancer is the most common cancer type worldwide referred to as HER2-positive. HER2 overexpression is linked and is considered a heterogeneous genomic disease in terms to an aggressive phenotype resulting in reduced disease-free of molecular markers, prognosis, and treatments [1, 2]. At and overall survival compared with other breast cancer the molecular level, at least five clinical subtypes have been subtypes, and different strategies have been developed to try defined: hormone receptor-positive (luminal A and luminal to block this receptor [5–9]. According to clinical data, B), human epidermal growth factor receptor-2 (HER2- HER2-targeted therapy significantly improves the survival of positive), basal-like, normal-like, and triple-negative breast breast cancer patients showing HER2 overexpression. cancer (TNBC) [2–4]. Based on this classification, the on- However, recent data suggest the presence of oncogenic cologist is able to prescribe the best endocrine therapy, mutations in HER2 affects clinical outcome in HER2-pos- chemotherapy (alone or combined), and/or HER2-targeted itive breast cancer patients [10]. 2 Journal of Oncology In 1983, the receptor tyrosine kinase 2 gene (ERBB2 or identified in 4% of breast cancer patients; these mutations newly named HER2) was cloned [11]. *is gene is located on are independently associated with HER2 amplification status, occurring in both hormone receptor (HR)-positive/ the short arm of chromosome 17 and its product is the glycoprotein, HER2, which has several functional domains HER2-negative and HER2-positive [21, 27–30]. Some au- (Figure 1) that resemble those of other members of the thors suggest that the prevalence of HER2 mutations tyrosine kinase family (HER1, HER3, and HER4): an ex- changes according to certain histological subtypes in breast tracellular domain (ECD, containing four subdomains), a cancer [21, 27, 31]. transmembrane domain (TMD), an intracellular region that Recently, data from preclinical and clinical studies have consists of a juxtamembrane domain (JMD), and a tyrosine attributed somatic mutations in HER2, a role in the con- kinase domain (TKD) [12]. HER2 is an atypical member of stitutive expression [31–33] or differential regulation of the ERBB family because it has no known ligand and its ECD HER2 that leads to resistance (primary or acquired) to anti- constitutively adopts an open conformation [13]. *is has HER2 therapy and endocrine therapy [4, 6, 10, 34–36]. Such led several authors to suggest a role of HER2 as coreceptor mutations therefore undermine the clinical benefits of HER2-targeted treatment in HER2-positive breast cancer [14]. HER2 preferentially heterodimerizes with ligand bound untethered (open) HER3 or with HER4 and HER1, patients. Besides, different mutations in HER2 have been thereby affecting the downstream signaling of these recep- found in several tumors although their role in tumorigenesis tors. In overexpressing cells, HER2 forms homodimers that is not fully understood. To assess the possible clinical im- are capable of signaling [13, 15, 16]. HER2 promotes on- plications of HER2 mutations in HER2-positive breast cogenic signaling by modulating the expression and activity cancer patients, we here review the spectrum of single of proteins controlling cell proliferation, differentiation, nucleotide polymorphisms (SNPs) produced in the HER2 death, migration, and angiogenesis, activating specific PI3K/ gene. Our working hypothesis was that recurrent mutations Akt (phosphatidylinositol 3-kinase/Akt, also known as PKB, in specific HER2 domains in these patients could be good protein kinase B) and MAPK (mitogen-activated protein biomarkers of the efficacy of anti-HER2 therapy. kinase) pathways (Figure 2). Unlike other ERBB receptors, HER2 remains on the cell surface for prolonged periods after 2. Methods being activated to signal, which contributes to its ability to transform cells when overexpressed. New findings in breast To identify mutations in the HER2 gene in HER2-positive cancer cells indicate that plasma membrane calcium breast cancer patients, two databases were searched: cBio- ATPase2 (PMCA2) is vital for the localization of HER2 and Portal [37] and COSMIC [38]. *ese websites provide in- its partners, EGFR and HER3, to activate membrane sig- formation regarding the largest number of studies and HER2 naling domains contributing to HER2’s ability to transform mutations across different cancer types. To identify muta- cells when overexpressed and prevent HER2 internalization tions reoccurring in HER2-positive breast cancer, the fol- after receptor stimulation and it sustains downstream signal lowing keywords were used: HER2+ BREAST CANCER, transduction. *is means that targeting PMCA2-HER2 ER-HER2+ BREAST CANCER, and ER-PR-HER2+ interactions could be a new therapeutic approach [17]. BREAST CANCER. In both databases, mutations were Recently, HER2 and the cannabinoid receptor CB R have 2 observed at similar frequencies. To obtain functional data for been described to physically interact. In effect, the expres- the different mutations, we also undertook a PubMed [39] sion of heteromers (HER2-CB R) has been correlated with a 2 search for articles written in English using the keywords: poor prognosis, while their disruption promotes an anti- BREAST CANCER, CANCER RISK, HER2/ERBB2, HER2 tumor response suggesting these heteromers could be used POSITIVE, HER2-TYROSINE KINASE DOMAIN, HER2, as therapeutic targets and prognostic tools in HER2-positive HER2-TRANSMEMBRANE DOMAIN, HER2-EXTRA- breast cancer [18]. CELLULAR DOMAIN, and HER2 MUTATIONS. HER2 gene amplification, or protein overexpression, is still considered a major mechanism of HER2-driven tu- morigenesis and is used as a main predictive biomarker to 2.1. Mutations in HER2 Gene in Different Breast Cancer identify patients who might benefit from therapy with anti- Histologies. Mutations in the ERBB2 receptor described in HER2 agents. *ere are, thus, many different cancer drugs this study according to the tumor type were found in in- approved by the US Food and Drug Administration (FDA) vasive lobular carcinoma (ILC), invasive ductal carcinoma that target the deregulation of HER2, including monoclonal (IDC), and mixed ductal and lobular carcinoma (MDLC) antibodies, antibody-drug conjugates, and small-molecule (Table 2). *ere is variability in the distribution of the TKIs (tyrosine kinase inhibitors), such as trastuzumab, different mutations depending on the specific histology of pertuzumab, lapatinib, trastuzumab-emtansine (T-DM1), the breast cancer type. Seven of the eleven mutations were and neratinib [19–21], as well as others under investigation present in both types of carcinomas or even in mixed such as afatinib [7, 22–25] (Table 1). Molecular studies have carcinomas (MDLC); however, some of these mutations are shown that HER2-positive breast cancers are heterogeneous mainly found in IDC or others in ILC (Table 2). *us, and that the different tumors may be classified as HER2- mutations located mainly in IDC were D769H, V842I, enriched or luminal molecular subtypes based on estrogen K753E, R678Q, and S310F I655V. In the other side, mu- receptor expression (ER), with implications in their response tations more prevalent in ILC were L755S, V777L, D769Y, to targeted therapies [26]. Furthermore, HER2 mutations are and S310Y. Previous studies suggest that HER2 mutations Journal of Oncology 3 N-terminal tail Subdomain I (L1): Coordinates: 52-173 Subdomain II (CR1): Furin-like L1 cysteine-rich region. Extracellular domain (ECD) Coordinates: 52-643 Coordinates: 183-343 CR1 Subdomain III (L2): Coordinates: 366-486 L2 Subdomain IV (CR2): Growth factor receptor domain. CR2 Coordinates: 510-643 Extracellular region Transmembrane domain (TMD) Coordinates: 649-675 Intracellular region JMD Juxtamembrane domain (JMD) Coordinates: 675-714 N N lobe C-α helix C C lobe Tyrosine kinase domain (TKD) Coordinates: 720-976 C-terminal tail Figure 1: Structural domains of HER2 protein. II II Pertuzumab ECD III Trastuzumab III IV IV TMD Neratinib N N Lapatinib TKD C C Afatinib C-terminal Cell cycle MAPK PI3K/Akt Proliferation HER2 degradation Cell growth Figure 2: *e mechanism of action of different drugs (italics and striped) on HER receptor signaling pathways. HER: human epidermal growth factor receptor; MAPK: mitogen-activated protein kinase; PI3K: phosphatidylinositol 3-kinase; Akt: serine/threonine kinase Akt, also known as PKB (protein kinase B); ECD: extracellular domain; TMD: transmembrane domain; TKD: tyrosine kinase domain. are enriched in certain histological subtypes, as example, quantitative analysis of the presence of specific mutations some authors have indicated that invasive lobular breast according to tumor type has been performed in this study, cancer (ILC), which composes about 15% of estrogen re- but the HER2 mutations described here located in IDC and ceptor- (ER-) positive subtype, the prevalence of HER2 ILC are in agreement with other studies [27, 31, 56, 57]. mutations is higher (cBioPortal-21, 27, 56-ILC). No Interestingly, in silico analysis suggests that some HER2 4 Journal of Oncology Table 1: Current therapeutic approaches targeting HER2 signaling [7, 22–25]. Drug Molecular target Molecular mechanism Treatment options TKD⟶ HER2 and HER1 Reversible inhibitor of HER1 and With metastasis: Lapatinib ATP mechanism of action HER2 trans- and +capecitabine or letrozole binding sites autophosphorylation +trastuzumab Irreversible inhibitor of HER1, TKD⟶ HER1, HER2, and Neratinib HER2, and HER4 trans- and Adjuvant after trastuzumab treatment HER4 ATP binding sites autophosphorylation Subdomain IV of HER2 Inhibitor of HER2 Trastuzumab First-line anti-HER2 treatment ECD homodimerization Ado-trastuzumab Inhibitor of HER2 Subdomain IV of HER2 Specific cases after anti-HER2 treatment with emtansine homodimerization, cytotoxic ECD trastuzumab (T-DM1) action of emtansine Dual therapy: anti-HER2 with Inhibitor of HER2 Pertuzumab Subdomain II of HER2 ECD trastuzumab + docetaxel/paclitaxel heterodimerization or + capecitabine/vinorelbine Under research: used as monotherapy in patients Irreversible inhibitor of HER1, TKD: HER1, HER2, HER4 with HER2-positive breast cancer showing Afatinib HER2, and HER4 trans- and ATP binding sites progression despite trastuzumab treatment. autophosphorylation Pending FDA approval TKD: tyrosine kinase domain; ECD: extracellular domain; HER2: human epidermal growth factor receptor 2. mutations are enriched in primary ILC and their detection of signaling proteins such as phospholipases cC1 and Cc represents an actionable strategy with the potential to im- (PLCc) MAPK. Many of these activating mutations have prove patient outcomes with estrogen receptor-positive, proved resistant to anti-HER2, such as those found at codons ERBB2 nonamplified primary lobular [27]. Overall, more 755 or 798 [34]. quantitative studies are needed for the identification of co- Most authors have described the appearance of both occurring and mutually exclusive HER2 mutations intrinsic and acquired resistance to trastuzumab therapy in according to histology subtype in order to identify patient mutations L755S, V777L, D769Y, and K753E that could potentially be targeted with HER2-directed [32, 40, 42, 44, 45]. As these mutations are not located close to the drug’s binding target, it seems that rather than therapies. blocking receptor binding of the drug, they affect resistance to its effects by increasing kinase activity and activation of 2.2. Mutations in the Tyrosine Kinase Domain. Most muta- the protein’s oncogenic signaling pathways, independently tions in the HER2 gene have been detected in exons 19 and of drug binding. All these mutations as well as D769H share 20 of the tyrosine kinase (TK) domain, at the C-α helix the feature of sensitivity to the actions of the irreversible TK position of the protein [34] (Table 2). Several authors inhibitor, neratinib [28, 30, 35, 41, 42, 45]. *is could be propose that mutations in this domain could be an alter- explained by the greater strength of interactions produced native mechanism to HER2 activation and affect sensitivity between this drug and the ATP-binding site. *is response offers a good treatment option for patients who may have to anti-HER2 therapy, as an acquired resistance mechanism to this form of therapy. *e TKD mutations described to developed resistance to first-line treatments for HER2+ breast cancer. Most authors agree that resistance to lapa- date in HER2+ breast cancer promote the activation of the functionality of the protein and increase the oncogenicity of tinib, both intrinsic and acquired, appears in L755S, D769Y, HER2, besides inducing the phosphorylation of other cell V842I, and K753E [41, 42, 44]. *is indicates the importance signaling proteins [28, 34] (Table 2). *is is because this of the electrostatic interactions that occur at the ATP domain contains the ATP binding site and its mutations are binding site close to these residues. Moreover, depending on related to the enhanced phosphorylation of receptors HER2, the changes produced by the amino acid substitutions, a HER3, and HER1, which causes receptor HER2 dimerization protein conformation may arise that promotes either the along with protein ERK (extracellular signal-regulated kinase) active state of HER2’s kinase domain impairing proper drug and AKT phosphorylation, with consequent activation of binding or this binding increases sensitivity toward the drug. *e L755S mutation is the most common in HER2 gene the PI3K/Akt and MAPK pathways, finally enhancing cell proliferation and angiogenesis (Figure 2). *e binding site of [41] and is considered a hotspot mutation [58]. *e protein’s codon 755 seems to be strongly involved in activating HER2 ATP with the receptor protein forms a conformational structure with other important structures such as phosphate receptor kinase, which leads to the potentiated activity of the activation and binding loops, which could be affected by such PI3K/Akt and MAPK signaling pathways, giving rise to modifications. Missense substitutions usually occur at the C-α enhanced cell proliferation and angiogenesis. In preclinical helix, which is essential for HER2 protein activation. *ese trials, this mutation has been associated with resistance to alterations can promote tumorigenesis and phosphorylation lapatinib treatment through reactivation of HER2 signaling Journal of Oncology 5 Table 2: Main features and pharmacological implications of the HER2 gene SNPs reviewed in HER2-positive breast cancer patients. ILC: invasive lobular carcinoma; IDC: invasive ductal carcinoma; MDC: mixed ductal and lobular carcinoma. *ese mutations are found also in HER2-negative breast cancer [28, 29, 32, 34, 77]. Tumor Mutation Mutation Exon Protein domain Pharmacological implications Study design References type impact Trastuzumab/lapatinib Breast cancer HER2+ resistance [40, 41] patients, in vitro studies Neratinib/afatinib sensitivity ILC Breast cancer HER2+ Lapatinib resistance [42, 43] L755S 19 IDC TKD, C-α helix Activation patients, in vitro studies MDC Trastuzumab resistance MANO method and [44] Afatinib/neratinib sensitivity xenograft MANO method and Afatinib/neratinib sensitivity [41, 44] xenograft Trastuzumab resistance Breast cancer HER2+ patients [45] Lapatinib/neratinib sensitivity Trastuzumab resistance MANO method and ILC TKD, C-α helix, Lapatinib/neratinib/afatinib [44] V777L 20 Activation xenograft IDC C-terminal tail sensitivity Trastuzumab + lapatinib Breast cancer HER2+ patient [31] sensitivity Neratinib sensitivity Breast cancer HER2+ patient [35] Neratinib sensitivity Trastuzumab/lapatinib Xenograft study [42] ILC resistance D769Y 19 TKD, C-α helix Activation IDC Trastuzumab resistance MANO method and Afatinib/lapatinib/neratinib [44] xenograft sensitivity Neratinib sensitivity Breast cancer HER2+ patient [28] Trastuzumab/pertuzumab Breast cancer HER2+ patient [46] D769H 19 IDC TKD, C-α helix Activation sensitivity Trastuzumab/afatinib/ MANO method and [44] lapatinib/neratinib sensitivity xenograft In vitro breast cell cultures; IDC Trastuzumab/lapatinib/ MANO method; I767M 19 ILC TKD, C-α helix Inconclusive [44, 47] afatinib/neratinib sensitivity xenotransplant; breast cancer MDLC HER2+ patients IDC Lapatinib/trastuzumab MANO method and V842I 21 TKD, c-loop Activation [44] ILC resistance xenograft Lapatinib/trastuzumab Likely K753E 18 IDC TKD, C-α helix resistance Breast cancer HER2+ tumors [32, 41] neutral Neratinib sensitivity Trastuzumab/lapatinib/ MANO method and R678Q 17 IDC JMD Activation afatinib/ [44] xenograft Neratinib sensitivity Trastuzumab sensitivity [48] No correlation with [49–51] trastuzumab efficacy Trastuzumab resistance [52] I655V 16 IDC TMD Activation No correlation with Breast cancer HER2+ patients trastuzumab-induced [53] cardiotoxicity Correlation with trastuzumab- [50] induced cardiotoxicity Neratinib/trastuzumab ECD, subdomain Breast cancer HER2+ patients [33, 54] IDC sensitivity S310F 8 II, furin-like Activation ILC Trastuzumab/lapatinib/ MANO method and domain CR1 [44] afatinib/neratinib sensitivity xenograft Neratinib/trastuzumab ILC ECD, subdomain Breast cancer HER2+ patients [33, 55] sensitivity S310Y 8 II, furin-like Activation IDC Trastuzumab/lapatinib/ MANO method and domain CR1 [44] MDLC afatinib/neratinib sensitivity xenograft 6 Journal of Oncology described. Considering that this last drug, as does trastu- in HER2+ breast cancer models in which the gene is overexpressed [43, 44]. In in vitro models, it was observed zumab, binds to the extracellular domain of the protein and that resistance to trastuzumab has been described, we would that cells with this mutation were resistant to treatment with lapatinib + trastuzumab, but also to trastuzu- expect pertuzumab to neither elicit a good response in mab + pertuzumab treatment [32, 40, 41]. As this mutation patients with this mutation. As occurs with the L755S induces resistance to trastuzumab alone or in combination mutation, HER2 V777L shows strong activation of the with pertuzumab, despite its location far from the drugs’ receptor’s kinase that could preserve its signaling activity binding sites on the receptor, it could be that kinase activity even with trastuzumab and pertuzumab bound to the ex- is so enhanced that it is able to continue signaling despite the tracellular domain of the protein. Interestingly, V777L and L755S mutants have been nondimerization of the receptor after the binding of these drugs [40, 41, 44, 59]. Resistance to lapatinib can be characterized using molecular dynamics simulations and in vitro studies in Ba/F3 cells expressing these mutants, explained by the fact that Leu 755 participates in hydro- phobic interactions with the C-α helix of the TKD in the showing that these mutants have a larger binding pocket volumes and therefore are more sensitive to tyrosine kinase active state of HER2, while in the inactive form, L755 is found far from this helix [43]. *e L755S polymorphism inhibitors (TKIs) of quinazoline (afatinib and poziotinib) induces the appearance of polar interactions that stabilize and indole (osimertinib and nazartinib) groups. Further- the active form; this would help explain resistance to more, in preclinical models, poziotinib upregulates HER2 lapatinib, which only binds to the inactive conformation of cell surface expression and potentiates the activity of HER2 [43]. *is resistance could be addressed with irre- T-DM1, inducing a complete tumor regression with com- versible HER1 and HER2 inhibitors such as neratinib, which bination treatment [62]. *e authors of this study suggest that poziotinib in combination with T-DMI could be a good has proven effective in patients with this mutation [41]. In effect, in vitro studies have shown the sensitivity of cells with candidate treatment for not only non-small cell lung cancer; in fact, one ongoing trial in phase II is studying the efficacy of the L755S mutation to afatinib plus neratinib [41, 44]. Be- sides intrinsic resistance, mutation L755S has been associ- poziotinib in metastatic breast cancer harboring HER2 mutations [21, 62]. Overall, more clinical studies are needed ated with resistance acquired to trastuzumab therapy in breast cancer. It appears in 7.59% of patients receiving prior to test the efficacy of poziotinib in combination with T-DMI trastuzumab treatment. Further, it has been reported to in breast cancer to rule out differences in tumor type-specific occur in 3 out of every 18 patients with metastasis but not sensitivities to the same pharmacological product. In those with primary tumors [41]. SUMMIT trial, neratinib was most effective in breast cancer Mutation V777L is also considered hotspot [58]. Res- patients, with patients containing L755S and V777L [33], but idue V777L, located in exon 20 (at the C-terminal tail of the the same mutations were associated with resistance in other cancer types, suggesting that more research is needed to C-α helix), is involved in TK activity. *is activating mu- tation promotes the TK activity of HER2, increasing the identify the mechanism involved in tumor-type-specific sensitivities. phosphorylation of signaling proteins such as HER2, HER3, EGFR, and ERK, and the transformation of breast epithelial Recently, using isogenic knock-in HER2 mutations in cells [29, 33, 40, 45, 60]. *is mutation causes transcrip- ER + MCF7 cells and xenografts, two activating HER2 tional activation in most tumors affected by this mutation, mutations located in the kinase domain (L755S and V777L) which usually occurs independently of HER2 gene activa- emerged as resistance to anti-ER therapy progression [35]. tion [60]. In effect, cases have been described in breast *ese findings are corroborated by other authors, and the cancer cell lines in which increased endogenous expression same mutations have been identified in metastatic biopsies levels of HER2 V777L activated signal transduction path- of eight patients with ER + metastatic breast cancer (MBC), ways, but this did not significantly increase tumor growth as mutations that were acquired under the selective pressure of ER-directed therapy such as aromatase inhibitors [36]. [61]. *e effects of V777L seem enhanced by mutations in the PIK3CA gene given that, in the presence of mutation *e same authors demonstrated that the resistance to ER- directed therapy was overcome by combining fulvestrant PIK3CA E545K, V777L gives rise to enhanced interaction between p58 and HER3. *is suggests that reverse muta- with the irreversible HER2 kinase inhibitor neratinib. *ese tions of the HER2 gene could require other genetic alter- data suggest that the prevalence of HER2 mutations might ations to promote cellular transformation and enhance increase in metastatic ER+ breast cancer treated with anti- interactions between signaling partners [31]. *is mutation ER therapy, and these mutations are a distinct mechanism of has been associated with the intrinsic development of acquired resistance to ER-directed therapy in metastatic trastuzumab resistance [45]. Although the mutation has breast cancer that could be solved by the treatment with an irreversible HER2 inhibitor. Overall, these data suggest that been associated in some preclinical studies with a dimin- ished response to lapatinib, afatinib, and neratinib, several patients with ER+/HER2 mutations would benefit from HER2-targeted therapies in combination with hormonal studies have shown reduced tumor growth and signaling activity in tumors with the V777L mutation treated with therapy. If ongoing clinical trials confirm these results, new approaches could be adopted in order to promote a better lapatinib [44, 45]. A response has been observed to com- bined treatment with neratinib and other drugs in patients response in patients with ER + MBC, and one of these with ER + V777L breast carcinoma [35]. No cases relating strategies could be to identify HER2-mutant-resistant clones this mutation to the response to pertuzumab have been to ER-directed therapy [36]. Journal of Oncology 7 observed in cell lines overexpressing HER2 K753E. In HER2 Mutation V842I has been detected in various types of tumor tissue. *is is also an activating mutation associated K753E mutant cells resistant to lapatinib, a greater affinity of the drug for the HER2 protein was observed compared to with HER2 gene amplification and increased phosphoryla- tion of different signaling proteins [28] and also represents a wild-type cells and other variants. *is reveals that resistance hotspot in HER2 [58]. to this drug is unrelated to a lack of binding to its target [63]. *e effects of V842I on the response to anti-HER2 It has also been related to resistance to trastuzumab and therapy in patients with HER2+ breast cancer have not been appears in 2 out of every 18 patients with metastasis [32]. yet explored. Some in vitro studies indicate the resistance to While cell lines that show this mutation are resistant to trastuzumab and lapatinib of cell lines with this mutation lapatinib, they are sensitive to neratinib, which could benefit patients developing resistance to trastuzumab therapy [41]. [44]. *is mutation is the most common mutation in co- lorectal cancers, and in vitro studies have shown that this Following trastuzumab therapy, the appearance of K753E and L755S mutants could suggest their potential role mutant was not sensitive to neratinib [62]. However, given its recurrent expression in different tumor tissues and its as drivers of developing trastuzumab resistance during HER2+ tumor progression [32]. association with amplification of the gene, studies are warranted to clarify its impact on the receptor’s kinase Mutation I767M is a hotspot in gene HER2 [58] iden- activity. tified in patients with HER2+ breast cancer [54]. Its ex- *e nonsynonymous mutations D769Y and D769H are pression has been examined in vitro in HER2- among the most frequent somatic mutations of the HER2 overexpressing mammary cell lines and in HER2-negative gene. *ey are located in exon 19, at position 769 of the TK cultures. In the former cells, the presence of this mutation domain, which is important for ATP-HER2 binding [29]. along with mutations in the genes PIK3CA and TP53 conferred a significant growth benefit over cells with the Both mutations have been characterized as activators in mammary epithelium cell lines, and in vivo studies have wild-type HER2 gene. Further, both the mutant and wild- type protein featured similar AKT and MAPK signaling revealed neratinib as effective at blocking tumor growth in HER2+ breast carcinomas with these mutations [28, 42]. levels, although the AKT pathway remained active over time for longer in the cells expressing HER2 I767M [47]. In Cases have been described of xenografts acquiring the D769Y mutation following treatment with trastuzumab, vitro studies conducted by Nagano et al. [44] indicate the along with their subsequent resistance to trastuzumab and sensitivity of I767M to therapy with both TK inhibitors lapatinib, suggesting its possible role in acquired resistance (lapatinib, neratinib, and afatinib) and the monoclonal to anti-HER2 therapy [42]. In mutation D769Y, the change antibody trastuzumab. from aspartic acid to tyrosine could lead to changes in According to the data from COSMIC and cBioPortal, electrostatic interactions, due to the substitution of a neg- while other mutations in this kinase domain have been described (i.e., V797A, D808E, D873G, and M889I), there atively charged acid side chain at physiological pH with the capacity to form hydrogen bridges and bind phosphate are still no data regarding their role in HER2+ breast cancer. groups. As this mutation occurs at an important position for ATP binding to the receptor, this change could benefit this 2.3. Mutations in the Juxtamembrane Domain. *e juxta- binding and thus diminish the impacts of lapatinib and membrane domain, containing 39 amino acids (Figure 1), is neratinib therapy, whose mechanism of action is to impair involved in receptor dimerization and stability. Several this binding of ATP to HER2 [42]. *e D769Y mutation authors have described reoccurring mutations in this do- promotes the phosphorylation of HER2, EGFR, HER3, and main with a functional activating effect in different cancer ERK and transformation of mammary epithelial cells. Cell types [10]. However, these studies do not specify if these lines with this mutation display sensitivity to neratinib, in mutations occur in patients with HER2-positive breast smaller measure to lapatinib and resistance to trastuzumab cancer. In our search of mutations in the COSMIC and [42], although Nagano et al. recently described sensitivity to cBioPortal databases, we found two mutations, R678Q and lapatinib and afatinib in in vitro studies [44]. Some authors V697L, present in HER2-positive breast carcinoma. In vitro report that loss of the acid side chain or addition of an studies indicate that R678Q is an activating mutation that aromatic ring to amino acid 769 could increase HER2’s TK confers sensitivity towards treatment with trastuzumab, activity due to dimeric interactions between the kinase lapatinib, afatinib, and neratinib (Table 2) [10, 33, 44] and domains of HER2 and HER3. Mutations D769H/Y may has been classified as a hotspot [64]. No functional data exist enhance hydrophobic contacts and heterodimerization of for mutation V697L, but it has been described as a muta- HER2. Besides, the D769H alteration could lead to activation tional hotspot and data available for other cancer types within the HER2 monomer, adding hydrogen bonds to its suggest its oncogenic effect. own activation A-loop [46, 54]. Mutation K753E leads to a shift in charge of the amino 2.4. Mutations in the Transmembrane Domain. *e trans- acid’s side chain, which goes from being basic to acidic, thus possibly affecting the electrostatic interactions of the protein. membrane domain of receptor HER2 (aa 649–675, Figure 1) plays an active role in its dimerization with the consequent Several authors have related this mutation with lapatinib resistance, and this could be attributed to its close proximity activation of kinase activity and promotion of the signaling with the L755S mutation which confers resistance to this pathways responsible for tumor cell growth. Recently, re- drug [32, 41]. Recently, the effect of this mutation has been current mutations have been identified with an activating 8 Journal of Oncology dimerization of the receptor, kinase activation, and malig- effect in different cancers [10]. However, the data sources COSMIC and cBioPortal reveal that no mutations in this nant cell transformation. Both mutations appear to have a homologous effect. Of the two, S310F has been most studied domain occur in HER2-positive breast cancer. In the present study, we identified only one mutation, I655V (Table 2), in in different tumor tissues (both HER2-positive breast and HER2-positive patients, which, according to Fleishman et al. HER2-negative lobular breast, lung, colorectal, ovarian, [65], involves an altered receptor conformation that renders bladder, micropapillary urothelial, and endometrial) it a constitutively activated state, promoting the homo- [29, 33, 54, 68–70] while S310Y has been more commonly dimerization and autophosphorylation of HER2 and acti- associated with pulmonary adenocarcinoma while it has vation of the TK domain [65]. Singla et al. [49] found, among been also found in HER2-positive and HER2-negative breast cancer [29, 33, 55, 71]. *e fact that mutations in this po- patients in Indian hospitals, a positive significant association between HER2 I655V and the susceptibility of developing sition are present in different cancers suggests it could be an oncogenic mutation [72]. *ey are therefore mutations that breast cancer, while other authors have detected negative correlation when examining patients in Brazil [66]. A meta- activate HER2 protein via elevated phosphorylation of the C-terminal tail, as is the case of mutation S310F/Y, or in- analysis conducted in 2019 [67] revealed the impacts of ethnicity on the association between mutation HER2 I655V ducing covalent dimerization sustained by intermolecular and breast cancer risk, observing positive correlation in Asia disulfide bridges [73], as in the case of mutations G309E/A, and Africa but not the other continents. only described in HER2-negative breast cancer and other *e relationship between this mutation and the response cancers [28, 73]. In the presence of an S310F/Y mutation, it to trastuzumab-containing chemotherapy in HER2-positive has been noted that protein HER2 seems more sensitive to breast cancer patients has been examined, yet results have anti-HER2 therapy containing neratinib and possibly tras- tuzumab in patients with HER2+ breast cancer [33, 54, 55]. been contradictory. In some studies, disease-free survival (DFS) and delayed DFS (DDFS) were improved in patients Accordingly, in cells featuring ECD mutations, trastuzumab may bind to this region and prevent homodimerization and with this mutation and the genotypes HER2 Val/Val or Val/ Ile compared to the genotype Ile/Ile [48]. On the contrary, activation of the receptor. However, because of the constant activation of the TKD in tumors with mutations at this Furrer et al. [52] noted a worse response to trastuzumab- containing chemotherapy, while other studies have found no domain, the antiproliferative effects of monoclonal anti- correlation [49–51]. *ese results preclude establishing a bodies may be limited despite inhibiting dimerization [74]. clear relationship between this polymorphism and the de- *e effects of these mutations on the response to pertu- velopment of resistance to treatment with trastuzumab. *e zumab and trastuzumab have been investigated recently effect of trastuzumab and other antibodies may be limited in using in vitro 5637 culture cells and single-molecule in- tumors that show mutations in the TMD, as HER2 di- teraction analyses using TIRF microscopy [74]. *e overexpressed S310F as well as G309A, G309E, and S310Y merization seems stable despite trastuzumab binding to its extracellular domain. Neratinib, which binds to the HER2 HER2 mutants reacted to trastuzumab, but S310F mutant did not react to pertuzumab along with S310Y or G309E receptor’s kinase domain and inhibits its phosphorylation and activity, can exert antitumor effects irrespective of the mutants. *ereafter, authors tested the effects of trastu- domain affected by mutations and has an impact on this zumab and pertuzumab using both wild-type HER2 and HER2 I655V mutation in different lung cancer cell lines [68]. S310F mutant. In this case, trastuzumab did not inhibit the Something similar occurs with the risk of cardiotoxicity activation of the HER2 receptor, suggesting that the S310F induced by trastuzumab. Despite initial proposals that being HER2 mutant did not form homodimers or heterodimers a carrier of the mutant allele, genotypes HER2 Val/Val or with wild-type HER2. Because pertuzumab did not inhibit Val/Ile, was a possible predictor of this adverse effect of the the phosphorylation of HER2 while it bound to wild-type drug [50], this relation could not be later confirmed [53]. HER2, EGFR-mediated phosphorylation is expected to occur on the S310F mutant; therefore, trastuzumab in Some authors have suggested that carrying this mutation only affects the survival of patients with breast cancer who combination with pertuzumab is not effective [74]. *is residue is located close to one of the key residues, K311, for overexpress the HER2 gene [48]. To date, the possible effect of this mutation on the actions of other HER2-target drugs receptor-antibody binding whose replacement with ala- such as pertuzumab, neratinib, afatinib, or lapatinib has not nine, via targeted mutagenesis, leads to a drastic reduction been addressed. in the response to this drug in cells expressing the muta- tion. Amino acid substitutions in these residues could provoke changes in electrostatic interactions or even give 2.5. Mutationsin theExtracellularDomain. *e extracellular rise to a stearic impediment possibly affecting pertuzumab domain is composed of four subdomains involved in di- binding to the HER2 receptor [69]. merization of the receptor and thus in its activation. Several Other less frequent mutations in the ECD have been described, such as R190Q, P523S, and Q548R, in patients mutations in the ECD domain have been described in pa- tients with HER2-positive breast cancer both in PubMed and with breast cancer without specifying HER2 amplification, in which no relationship has been found between the mu- the databases COSMIC and cBioPortal, as described below. *e most common mutations in the ECD of the HER2 tations and prognosis [75]. Even rarer are L313I and R456C, receptor, S310F and S310Y, corresponding to the gene observed in two patients with HER2+ breast cancer effec- hotspot (Table 2) [64], have been related to the increased tively treated with neratinib [42]. Journal of Oncology 9 data available for HER2-negative breast cancer patients *e COSMIC and cBioPortal databases also describe other mutations in this domain about which there are no (Table 3), functional activating HER2 mutations, V777L, L755S, S310F, D769H/Y, and V842I, may similarly confer published data for HER2-positive breast cancer: A37T, P232S, D277H (also described in bladder cancer, enhances sensitivity to HER2-directed pharmacological products. its activation together with S310F, de Martino et al. [76]), Furthermore, a high number of HER2-mutant tumors are T297I, E405D, and H470Q. also ER+, and as discussed before, the most effective treatment will be combining fulvestrant with the irreversible inhibitor neratinib [21, 35]. Overall, HER2-negative breast 2.6. Beyond HER2+ Breast Cancer: Lessons from Clinical cancer patients carrying the above mutations can benefit Data from the Use of HER2-Directed ?erapy against HER2 from HER2-targeted therapy; this is in agreement with data Mutant Cancers. Around sixteen clinical trials investigating previously published by other authors [32, 78]. the efficacy of HER2-directed therapy in HER2 mutant cancers are currently active [21]. Four phase II studies are studying the efficacy of different pharmacological products 2.7. Conclusions and Future Perspectives. Research and (afatinib, neratinib plus trastuzumab, poziotinib, and clinical studies have shown that HER2 overexpression/ pyrotinib) in different types of metastatic HER2 non- amplification is associated with poor survival in breast amplified but with HER2 mutant breast cancer. *ere are a cancer patients. Further, in vitro and in vivo studies indicate relatively large number of pharmacological approaches for that the presence of somatic HER2 mutations could influ- breast cancer carrying HER2 mutants. In part, we have ence the clinical outcome of HER2-positive patients under reached this situation because activating mutations for currently approved treatments (Table 1). New findings in HER2 have been shown to be largely dependent on tumor breast cancer cells suggest that HER2 could interact phys- ically with PMCA2 and the cannabinoid receptor CB histology and have shown different clinical responses. Some R. mutations are sensitive in a specific type of cancer and in Hence, targeting these heteromers could be a new thera- others could be associated with resistance, suggesting that peutic option and prognostic tool in HER2-positive breast there may be other mechanisms specific with the tumor that cancer. Recently, in vitro and in vivo studies in metastatic requires further research. ER + tumors suggest that some HER2 mutations emerge as a *e focus of this review is to assess the possible clinical mechanism of acquired resistance to endocrine therapy implications of HER2 mutations in HER2-positive breast opening new options of treatments in patients with cancer patients; in this study, we have described that the ER + MBC. most prevalent mutations found in HER2 gene in HER2- In this review, we identify the more prevalent somatic positive breast cancer (Table 2) are present also in HER2- HER2 SNP mutations appearing in HER2-positive breast negative breast cancer [28, 29, 32, 34, 57]. We would like to cancer patients and summarize their possible implications address, using clinical data available, if HER2-negative pa- for current HER2-targeted therapy (Figure 4). We found tients with HER2 somatic mutations are potentially good that somatic HER2 mutations occur in low frequency in candidates for HER2-directed therapy. *e clinical data HER2-positive breast cancer patients. In total, 11 somatic available have been reviewed by Cocco et al. [21] and are mutations have been identified, and according to infor- summarized in Table 3. *e first patient diagnosed with mation available from in vitro and in vivo studies, 9/11 are triple-negative breast cancer, carrying two HER mutations classified as oncogenic and hotspot (see Table 2), and several (V777L and S310F), respond to lapatinib and trastuzumab- authors have identified the presence of these mutations also based therapies during 6 months. A second case diagnosed in HER2-negative breast cancer patients. For two mutations, with ER + HER-negative breast cancer, carrying a HER2 I767M and K753E, there is insufficient information so far to S310F mutation, was treated during 12 months with the classify them as oncogenic and/or hotspot. In HER2-positive combination of trastuzumab, pertuzumab, and fulvestrant. tumors, the TKD harbored the higher number of somatic An additional case with ER+, HER2-negative metastatic mutations (7/11), contrasting with the low number of breast cancer with HER L755S mutation was treated with mutations found in the extracellular and transmembrane neratinib monotherapy experiencing improvement in domains. *e relevance of some mutations identified in this symptoms and tumor markers. Another case described a study requires further investigation. HER2 (D769H) mutant with metastatic HER2-negative For the reviewed somatic HER2 mutations, no sensitivity breast who achieved a partial response with trastuzumab, or resistance data are available for pertuzumab, with the pertuzumab, and chemotherapy (Table 3). *ese clinical data exception of mutation D769H. For some mutations, avail- are in agreement with the pharmacological profile of the able data are inconclusive requiring more functional studies. SNPs of HER2 reviewed in this study (Figure 3). In the phase HER2-positive patients carrying S310F, S310Y, R678Q, II MutHER trial, the activity of neratinib in HER2 mutant D769H, I767M, or V777L emerged as potentially good nonamplified metastatic breast cancer was investigated candidates for HER2-targeted therapy and could have a (Table 3); the patients obtained clinical benefit over 24 favorable outcome because of sensitivity to current phar- months [77]. A case report was a HER2-negative breast macological treatments with the exception of inconclusive cancer patient with two detected mutations in ERBB2 (S310F data for the impacts of trastuzumab in V777L (Figure 3). and D769Y mutations) who benefited from lapatinib Patients with L755S or D769Y might also benefit from combined with endocrine therapies [78]. Based on clinical neratinib or afatinib treatment. In contrast, patients with the 10 Journal of Oncology Table 3: Clinical response of HER2 mutant breast tumors to anti-HER2-based therapy. No. Type of breast cancer HER2 mutation Pharmacological treatment Outcome Reference patients V777L Improvement during 6 Reviewed in 1 Triple-negative Lapatinib, trastuzumab S310F months 21 Trastuzumab, pertuzumab Improvement during 12 Reviewed in 1 ER+/HER-negative S310F fulvestrant months 21 Improvement during 12 Reviewed in 1 ER+/HER-negative L755S Neratinib months 21 Metastatic HER2- Trastuzumab, pertuzumab Reviewed in 1 D769H Partial response negative chemotherapy 21 1 HER2-negative S310F/V842I Neratinib Benefit [77] 6 HER2-negative L755S Neratinib Benefit [77] 1 HER2-negative D769H Neratinib Benefit [77] 1 HER2-negative p.L755_T759del Afatinib, trastuzumab Response [78] 1 HER2-negative S310F and D769Y Lapatinib and endocrine therapy Response [78] Juxtamembrane Transmembrane Extracellular Tyrosine kinase domain domain domain domain L755S V777L D769Y D769H I767M V842I K753E R678Q I655V S310F/S310Y Trastuzumab Pertuzumab Lapatinib Neratinib Afatinib Resistant Inconclusive Sensitive No data Figure 3: Pharmacological impacts of the SNPs reviewed in this study. *e sensitivity of HER2 mutants to different drugs used as anti-HER2 therapy is shown. *e pharmacological products have different levels of activity against mutant HER2+ proteins in vitro. When data from in vivo studies (xenotransplant and/or breast cancer patients) were available, they were considered for the analysis. Furthermore, some mutants that have been described to be sensitive to specific inhibitors in preclinical analyses were instead found to be resistant to the same drugs; in this case, we have indicated this information as inconclusive data. L755S V777L I767M D769Y/H S310F/Y K753E R678Q V842I I655V III III IV TMD JMD TKD 0 200 400 600 800 1000 1250 aa Figure 4: Schematic diagram of HER2 protein with the locations of the SNPs reviewed in this study found in HER2-positive breast cancer patients. Domains I, II, III, and IV belong to the extracellular domain (ECD); TMD: transmembrane domain; JMD: juxtamembrane domain; TKD: tyrosine kinase domain. Journal of Oncology 11 [10] K. B. Pahuja, T. T. Nguyen, B. S. 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Somatic Mutations in HER2 and Implications for Current Treatment Paradigms in HER2-Positive Breast Cancer

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Hindawi Journal of Oncology Volume 2020, Article ID 6375956, 13 pages https://doi.org/10.1155/2020/6375956 Review Article Somatic Mutations in HER2 and Implications for Current Treatment Paradigms in HER2-Positive Breast Cancer Maria Gaibar , Laura Beltra´n , Alicia Romero-Lorca , Ana Ferna´ndez-Santander , and Apolonia Novillo Faculty of Biomedical Sciences and Health, Universidad Europea de Madrid, C/Tajo, S/N, 28670 Villaviciosa de Odo´n, Madrid, Spain Correspondence should be addressed to Apolonia Novillo; apolonia.novillo@universidadeuropea.es Received 28 October 2019; Revised 28 January 2020; Accepted 6 February 2020; Published 7 March 2020 Guest Editor: Cigdem Selli Copyright © 2020 Maria Gaibar et al. *is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In one of every four or five cases of breast cancer, the human epidermal growth factor receptor-2 (HER2) gene is overexpressed. *ese carcinomas are known as HER2-positive. HER2 overexpression is linked to an aggressive phenotype and a lower rate of disease-free and overall survival. Drugs such as trastuzumab, pertuzumab, lapatinib, neratinib, and the more recent afatinib target the deregulation of HER2 expression. Some authors have attributed somatic mutations in HER2, a role in resistance to anti-HER2 therapy as differential regulation of HER2 has been observed among patients. Recently, studies in metastatic ER + tumors suggest that some HER2 mutations emerge as a mechanism of acquired resistance to endocrine therapy. In an effort to identify possible biomarkers of the efficacy of anti-HER2 therapy, we here review the known single-nucleotide polymorphisms (SNPs) of the HER2 gene found in HER2-positive breast cancer patients and their relationship with clinical outcomes. Information was recompiled on 11 somatic HER2 SNPs. Seven polymorphisms are located in the tyrosine kinase domain region of the gene contrasting with the low number of mutations found in extracellular and transmembrane areas. HER2-positive patients carrying S310F, S310Y, R678Q, D769H, or I767M mutations seem good candidates for anti-HER2 therapy as they show favorable outcomes and a good response to current pharmacological treatments. Carrying the L755S or D769Y mutation could also confer benefits when receiving neratinib or afatinib. By contrast, patients with mutations L755S, V842I, K753I, or D769Y do not seem to benefit from tras- tuzumab. Resistance to lapatinib has been reported in patients with L755S, V842I, and K753I. *ese data suggest that exploring HER2 SNPs in each patient could help individualize anti-HER2 therapies. Advances in our understanding of the genetics of the HER2 gene and its relations with the efficacy of anti-HER2 treatments are needed to improve the outcomes of patients with this aggressive breast cancer. therapy. About 20–25% of all breast cancers overexpress 1. Introduction human epidermal growth factor receptor-2 (HER2) and are Breast cancer is the most common cancer type worldwide referred to as HER2-positive. HER2 overexpression is linked and is considered a heterogeneous genomic disease in terms to an aggressive phenotype resulting in reduced disease-free of molecular markers, prognosis, and treatments [1, 2]. At and overall survival compared with other breast cancer the molecular level, at least five clinical subtypes have been subtypes, and different strategies have been developed to try defined: hormone receptor-positive (luminal A and luminal to block this receptor [5–9]. According to clinical data, B), human epidermal growth factor receptor-2 (HER2- HER2-targeted therapy significantly improves the survival of positive), basal-like, normal-like, and triple-negative breast breast cancer patients showing HER2 overexpression. cancer (TNBC) [2–4]. Based on this classification, the on- However, recent data suggest the presence of oncogenic cologist is able to prescribe the best endocrine therapy, mutations in HER2 affects clinical outcome in HER2-pos- chemotherapy (alone or combined), and/or HER2-targeted itive breast cancer patients [10]. 2 Journal of Oncology In 1983, the receptor tyrosine kinase 2 gene (ERBB2 or identified in 4% of breast cancer patients; these mutations newly named HER2) was cloned [11]. *is gene is located on are independently associated with HER2 amplification status, occurring in both hormone receptor (HR)-positive/ the short arm of chromosome 17 and its product is the glycoprotein, HER2, which has several functional domains HER2-negative and HER2-positive [21, 27–30]. Some au- (Figure 1) that resemble those of other members of the thors suggest that the prevalence of HER2 mutations tyrosine kinase family (HER1, HER3, and HER4): an ex- changes according to certain histological subtypes in breast tracellular domain (ECD, containing four subdomains), a cancer [21, 27, 31]. transmembrane domain (TMD), an intracellular region that Recently, data from preclinical and clinical studies have consists of a juxtamembrane domain (JMD), and a tyrosine attributed somatic mutations in HER2, a role in the con- kinase domain (TKD) [12]. HER2 is an atypical member of stitutive expression [31–33] or differential regulation of the ERBB family because it has no known ligand and its ECD HER2 that leads to resistance (primary or acquired) to anti- constitutively adopts an open conformation [13]. *is has HER2 therapy and endocrine therapy [4, 6, 10, 34–36]. Such led several authors to suggest a role of HER2 as coreceptor mutations therefore undermine the clinical benefits of HER2-targeted treatment in HER2-positive breast cancer [14]. HER2 preferentially heterodimerizes with ligand bound untethered (open) HER3 or with HER4 and HER1, patients. Besides, different mutations in HER2 have been thereby affecting the downstream signaling of these recep- found in several tumors although their role in tumorigenesis tors. In overexpressing cells, HER2 forms homodimers that is not fully understood. To assess the possible clinical im- are capable of signaling [13, 15, 16]. HER2 promotes on- plications of HER2 mutations in HER2-positive breast cogenic signaling by modulating the expression and activity cancer patients, we here review the spectrum of single of proteins controlling cell proliferation, differentiation, nucleotide polymorphisms (SNPs) produced in the HER2 death, migration, and angiogenesis, activating specific PI3K/ gene. Our working hypothesis was that recurrent mutations Akt (phosphatidylinositol 3-kinase/Akt, also known as PKB, in specific HER2 domains in these patients could be good protein kinase B) and MAPK (mitogen-activated protein biomarkers of the efficacy of anti-HER2 therapy. kinase) pathways (Figure 2). Unlike other ERBB receptors, HER2 remains on the cell surface for prolonged periods after 2. Methods being activated to signal, which contributes to its ability to transform cells when overexpressed. New findings in breast To identify mutations in the HER2 gene in HER2-positive cancer cells indicate that plasma membrane calcium breast cancer patients, two databases were searched: cBio- ATPase2 (PMCA2) is vital for the localization of HER2 and Portal [37] and COSMIC [38]. *ese websites provide in- its partners, EGFR and HER3, to activate membrane sig- formation regarding the largest number of studies and HER2 naling domains contributing to HER2’s ability to transform mutations across different cancer types. To identify muta- cells when overexpressed and prevent HER2 internalization tions reoccurring in HER2-positive breast cancer, the fol- after receptor stimulation and it sustains downstream signal lowing keywords were used: HER2+ BREAST CANCER, transduction. *is means that targeting PMCA2-HER2 ER-HER2+ BREAST CANCER, and ER-PR-HER2+ interactions could be a new therapeutic approach [17]. BREAST CANCER. In both databases, mutations were Recently, HER2 and the cannabinoid receptor CB R have 2 observed at similar frequencies. To obtain functional data for been described to physically interact. In effect, the expres- the different mutations, we also undertook a PubMed [39] sion of heteromers (HER2-CB R) has been correlated with a 2 search for articles written in English using the keywords: poor prognosis, while their disruption promotes an anti- BREAST CANCER, CANCER RISK, HER2/ERBB2, HER2 tumor response suggesting these heteromers could be used POSITIVE, HER2-TYROSINE KINASE DOMAIN, HER2, as therapeutic targets and prognostic tools in HER2-positive HER2-TRANSMEMBRANE DOMAIN, HER2-EXTRA- breast cancer [18]. CELLULAR DOMAIN, and HER2 MUTATIONS. HER2 gene amplification, or protein overexpression, is still considered a major mechanism of HER2-driven tu- morigenesis and is used as a main predictive biomarker to 2.1. Mutations in HER2 Gene in Different Breast Cancer identify patients who might benefit from therapy with anti- Histologies. Mutations in the ERBB2 receptor described in HER2 agents. *ere are, thus, many different cancer drugs this study according to the tumor type were found in in- approved by the US Food and Drug Administration (FDA) vasive lobular carcinoma (ILC), invasive ductal carcinoma that target the deregulation of HER2, including monoclonal (IDC), and mixed ductal and lobular carcinoma (MDLC) antibodies, antibody-drug conjugates, and small-molecule (Table 2). *ere is variability in the distribution of the TKIs (tyrosine kinase inhibitors), such as trastuzumab, different mutations depending on the specific histology of pertuzumab, lapatinib, trastuzumab-emtansine (T-DM1), the breast cancer type. Seven of the eleven mutations were and neratinib [19–21], as well as others under investigation present in both types of carcinomas or even in mixed such as afatinib [7, 22–25] (Table 1). Molecular studies have carcinomas (MDLC); however, some of these mutations are shown that HER2-positive breast cancers are heterogeneous mainly found in IDC or others in ILC (Table 2). *us, and that the different tumors may be classified as HER2- mutations located mainly in IDC were D769H, V842I, enriched or luminal molecular subtypes based on estrogen K753E, R678Q, and S310F I655V. In the other side, mu- receptor expression (ER), with implications in their response tations more prevalent in ILC were L755S, V777L, D769Y, to targeted therapies [26]. Furthermore, HER2 mutations are and S310Y. Previous studies suggest that HER2 mutations Journal of Oncology 3 N-terminal tail Subdomain I (L1): Coordinates: 52-173 Subdomain II (CR1): Furin-like L1 cysteine-rich region. Extracellular domain (ECD) Coordinates: 52-643 Coordinates: 183-343 CR1 Subdomain III (L2): Coordinates: 366-486 L2 Subdomain IV (CR2): Growth factor receptor domain. CR2 Coordinates: 510-643 Extracellular region Transmembrane domain (TMD) Coordinates: 649-675 Intracellular region JMD Juxtamembrane domain (JMD) Coordinates: 675-714 N N lobe C-α helix C C lobe Tyrosine kinase domain (TKD) Coordinates: 720-976 C-terminal tail Figure 1: Structural domains of HER2 protein. II II Pertuzumab ECD III Trastuzumab III IV IV TMD Neratinib N N Lapatinib TKD C C Afatinib C-terminal Cell cycle MAPK PI3K/Akt Proliferation HER2 degradation Cell growth Figure 2: *e mechanism of action of different drugs (italics and striped) on HER receptor signaling pathways. HER: human epidermal growth factor receptor; MAPK: mitogen-activated protein kinase; PI3K: phosphatidylinositol 3-kinase; Akt: serine/threonine kinase Akt, also known as PKB (protein kinase B); ECD: extracellular domain; TMD: transmembrane domain; TKD: tyrosine kinase domain. are enriched in certain histological subtypes, as example, quantitative analysis of the presence of specific mutations some authors have indicated that invasive lobular breast according to tumor type has been performed in this study, cancer (ILC), which composes about 15% of estrogen re- but the HER2 mutations described here located in IDC and ceptor- (ER-) positive subtype, the prevalence of HER2 ILC are in agreement with other studies [27, 31, 56, 57]. mutations is higher (cBioPortal-21, 27, 56-ILC). No Interestingly, in silico analysis suggests that some HER2 4 Journal of Oncology Table 1: Current therapeutic approaches targeting HER2 signaling [7, 22–25]. Drug Molecular target Molecular mechanism Treatment options TKD⟶ HER2 and HER1 Reversible inhibitor of HER1 and With metastasis: Lapatinib ATP mechanism of action HER2 trans- and +capecitabine or letrozole binding sites autophosphorylation +trastuzumab Irreversible inhibitor of HER1, TKD⟶ HER1, HER2, and Neratinib HER2, and HER4 trans- and Adjuvant after trastuzumab treatment HER4 ATP binding sites autophosphorylation Subdomain IV of HER2 Inhibitor of HER2 Trastuzumab First-line anti-HER2 treatment ECD homodimerization Ado-trastuzumab Inhibitor of HER2 Subdomain IV of HER2 Specific cases after anti-HER2 treatment with emtansine homodimerization, cytotoxic ECD trastuzumab (T-DM1) action of emtansine Dual therapy: anti-HER2 with Inhibitor of HER2 Pertuzumab Subdomain II of HER2 ECD trastuzumab + docetaxel/paclitaxel heterodimerization or + capecitabine/vinorelbine Under research: used as monotherapy in patients Irreversible inhibitor of HER1, TKD: HER1, HER2, HER4 with HER2-positive breast cancer showing Afatinib HER2, and HER4 trans- and ATP binding sites progression despite trastuzumab treatment. autophosphorylation Pending FDA approval TKD: tyrosine kinase domain; ECD: extracellular domain; HER2: human epidermal growth factor receptor 2. mutations are enriched in primary ILC and their detection of signaling proteins such as phospholipases cC1 and Cc represents an actionable strategy with the potential to im- (PLCc) MAPK. Many of these activating mutations have prove patient outcomes with estrogen receptor-positive, proved resistant to anti-HER2, such as those found at codons ERBB2 nonamplified primary lobular [27]. Overall, more 755 or 798 [34]. quantitative studies are needed for the identification of co- Most authors have described the appearance of both occurring and mutually exclusive HER2 mutations intrinsic and acquired resistance to trastuzumab therapy in according to histology subtype in order to identify patient mutations L755S, V777L, D769Y, and K753E that could potentially be targeted with HER2-directed [32, 40, 42, 44, 45]. As these mutations are not located close to the drug’s binding target, it seems that rather than therapies. blocking receptor binding of the drug, they affect resistance to its effects by increasing kinase activity and activation of 2.2. Mutations in the Tyrosine Kinase Domain. Most muta- the protein’s oncogenic signaling pathways, independently tions in the HER2 gene have been detected in exons 19 and of drug binding. All these mutations as well as D769H share 20 of the tyrosine kinase (TK) domain, at the C-α helix the feature of sensitivity to the actions of the irreversible TK position of the protein [34] (Table 2). Several authors inhibitor, neratinib [28, 30, 35, 41, 42, 45]. *is could be propose that mutations in this domain could be an alter- explained by the greater strength of interactions produced native mechanism to HER2 activation and affect sensitivity between this drug and the ATP-binding site. *is response offers a good treatment option for patients who may have to anti-HER2 therapy, as an acquired resistance mechanism to this form of therapy. *e TKD mutations described to developed resistance to first-line treatments for HER2+ breast cancer. Most authors agree that resistance to lapa- date in HER2+ breast cancer promote the activation of the functionality of the protein and increase the oncogenicity of tinib, both intrinsic and acquired, appears in L755S, D769Y, HER2, besides inducing the phosphorylation of other cell V842I, and K753E [41, 42, 44]. *is indicates the importance signaling proteins [28, 34] (Table 2). *is is because this of the electrostatic interactions that occur at the ATP domain contains the ATP binding site and its mutations are binding site close to these residues. Moreover, depending on related to the enhanced phosphorylation of receptors HER2, the changes produced by the amino acid substitutions, a HER3, and HER1, which causes receptor HER2 dimerization protein conformation may arise that promotes either the along with protein ERK (extracellular signal-regulated kinase) active state of HER2’s kinase domain impairing proper drug and AKT phosphorylation, with consequent activation of binding or this binding increases sensitivity toward the drug. *e L755S mutation is the most common in HER2 gene the PI3K/Akt and MAPK pathways, finally enhancing cell proliferation and angiogenesis (Figure 2). *e binding site of [41] and is considered a hotspot mutation [58]. *e protein’s codon 755 seems to be strongly involved in activating HER2 ATP with the receptor protein forms a conformational structure with other important structures such as phosphate receptor kinase, which leads to the potentiated activity of the activation and binding loops, which could be affected by such PI3K/Akt and MAPK signaling pathways, giving rise to modifications. Missense substitutions usually occur at the C-α enhanced cell proliferation and angiogenesis. In preclinical helix, which is essential for HER2 protein activation. *ese trials, this mutation has been associated with resistance to alterations can promote tumorigenesis and phosphorylation lapatinib treatment through reactivation of HER2 signaling Journal of Oncology 5 Table 2: Main features and pharmacological implications of the HER2 gene SNPs reviewed in HER2-positive breast cancer patients. ILC: invasive lobular carcinoma; IDC: invasive ductal carcinoma; MDC: mixed ductal and lobular carcinoma. *ese mutations are found also in HER2-negative breast cancer [28, 29, 32, 34, 77]. Tumor Mutation Mutation Exon Protein domain Pharmacological implications Study design References type impact Trastuzumab/lapatinib Breast cancer HER2+ resistance [40, 41] patients, in vitro studies Neratinib/afatinib sensitivity ILC Breast cancer HER2+ Lapatinib resistance [42, 43] L755S 19 IDC TKD, C-α helix Activation patients, in vitro studies MDC Trastuzumab resistance MANO method and [44] Afatinib/neratinib sensitivity xenograft MANO method and Afatinib/neratinib sensitivity [41, 44] xenograft Trastuzumab resistance Breast cancer HER2+ patients [45] Lapatinib/neratinib sensitivity Trastuzumab resistance MANO method and ILC TKD, C-α helix, Lapatinib/neratinib/afatinib [44] V777L 20 Activation xenograft IDC C-terminal tail sensitivity Trastuzumab + lapatinib Breast cancer HER2+ patient [31] sensitivity Neratinib sensitivity Breast cancer HER2+ patient [35] Neratinib sensitivity Trastuzumab/lapatinib Xenograft study [42] ILC resistance D769Y 19 TKD, C-α helix Activation IDC Trastuzumab resistance MANO method and Afatinib/lapatinib/neratinib [44] xenograft sensitivity Neratinib sensitivity Breast cancer HER2+ patient [28] Trastuzumab/pertuzumab Breast cancer HER2+ patient [46] D769H 19 IDC TKD, C-α helix Activation sensitivity Trastuzumab/afatinib/ MANO method and [44] lapatinib/neratinib sensitivity xenograft In vitro breast cell cultures; IDC Trastuzumab/lapatinib/ MANO method; I767M 19 ILC TKD, C-α helix Inconclusive [44, 47] afatinib/neratinib sensitivity xenotransplant; breast cancer MDLC HER2+ patients IDC Lapatinib/trastuzumab MANO method and V842I 21 TKD, c-loop Activation [44] ILC resistance xenograft Lapatinib/trastuzumab Likely K753E 18 IDC TKD, C-α helix resistance Breast cancer HER2+ tumors [32, 41] neutral Neratinib sensitivity Trastuzumab/lapatinib/ MANO method and R678Q 17 IDC JMD Activation afatinib/ [44] xenograft Neratinib sensitivity Trastuzumab sensitivity [48] No correlation with [49–51] trastuzumab efficacy Trastuzumab resistance [52] I655V 16 IDC TMD Activation No correlation with Breast cancer HER2+ patients trastuzumab-induced [53] cardiotoxicity Correlation with trastuzumab- [50] induced cardiotoxicity Neratinib/trastuzumab ECD, subdomain Breast cancer HER2+ patients [33, 54] IDC sensitivity S310F 8 II, furin-like Activation ILC Trastuzumab/lapatinib/ MANO method and domain CR1 [44] afatinib/neratinib sensitivity xenograft Neratinib/trastuzumab ILC ECD, subdomain Breast cancer HER2+ patients [33, 55] sensitivity S310Y 8 II, furin-like Activation IDC Trastuzumab/lapatinib/ MANO method and domain CR1 [44] MDLC afatinib/neratinib sensitivity xenograft 6 Journal of Oncology described. Considering that this last drug, as does trastu- in HER2+ breast cancer models in which the gene is overexpressed [43, 44]. In in vitro models, it was observed zumab, binds to the extracellular domain of the protein and that resistance to trastuzumab has been described, we would that cells with this mutation were resistant to treatment with lapatinib + trastuzumab, but also to trastuzu- expect pertuzumab to neither elicit a good response in mab + pertuzumab treatment [32, 40, 41]. As this mutation patients with this mutation. As occurs with the L755S induces resistance to trastuzumab alone or in combination mutation, HER2 V777L shows strong activation of the with pertuzumab, despite its location far from the drugs’ receptor’s kinase that could preserve its signaling activity binding sites on the receptor, it could be that kinase activity even with trastuzumab and pertuzumab bound to the ex- is so enhanced that it is able to continue signaling despite the tracellular domain of the protein. Interestingly, V777L and L755S mutants have been nondimerization of the receptor after the binding of these drugs [40, 41, 44, 59]. Resistance to lapatinib can be characterized using molecular dynamics simulations and in vitro studies in Ba/F3 cells expressing these mutants, explained by the fact that Leu 755 participates in hydro- phobic interactions with the C-α helix of the TKD in the showing that these mutants have a larger binding pocket volumes and therefore are more sensitive to tyrosine kinase active state of HER2, while in the inactive form, L755 is found far from this helix [43]. *e L755S polymorphism inhibitors (TKIs) of quinazoline (afatinib and poziotinib) induces the appearance of polar interactions that stabilize and indole (osimertinib and nazartinib) groups. Further- the active form; this would help explain resistance to more, in preclinical models, poziotinib upregulates HER2 lapatinib, which only binds to the inactive conformation of cell surface expression and potentiates the activity of HER2 [43]. *is resistance could be addressed with irre- T-DM1, inducing a complete tumor regression with com- versible HER1 and HER2 inhibitors such as neratinib, which bination treatment [62]. *e authors of this study suggest that poziotinib in combination with T-DMI could be a good has proven effective in patients with this mutation [41]. In effect, in vitro studies have shown the sensitivity of cells with candidate treatment for not only non-small cell lung cancer; in fact, one ongoing trial in phase II is studying the efficacy of the L755S mutation to afatinib plus neratinib [41, 44]. Be- sides intrinsic resistance, mutation L755S has been associ- poziotinib in metastatic breast cancer harboring HER2 mutations [21, 62]. Overall, more clinical studies are needed ated with resistance acquired to trastuzumab therapy in breast cancer. It appears in 7.59% of patients receiving prior to test the efficacy of poziotinib in combination with T-DMI trastuzumab treatment. Further, it has been reported to in breast cancer to rule out differences in tumor type-specific occur in 3 out of every 18 patients with metastasis but not sensitivities to the same pharmacological product. In those with primary tumors [41]. SUMMIT trial, neratinib was most effective in breast cancer Mutation V777L is also considered hotspot [58]. Res- patients, with patients containing L755S and V777L [33], but idue V777L, located in exon 20 (at the C-terminal tail of the the same mutations were associated with resistance in other cancer types, suggesting that more research is needed to C-α helix), is involved in TK activity. *is activating mu- tation promotes the TK activity of HER2, increasing the identify the mechanism involved in tumor-type-specific sensitivities. phosphorylation of signaling proteins such as HER2, HER3, EGFR, and ERK, and the transformation of breast epithelial Recently, using isogenic knock-in HER2 mutations in cells [29, 33, 40, 45, 60]. *is mutation causes transcrip- ER + MCF7 cells and xenografts, two activating HER2 tional activation in most tumors affected by this mutation, mutations located in the kinase domain (L755S and V777L) which usually occurs independently of HER2 gene activa- emerged as resistance to anti-ER therapy progression [35]. tion [60]. In effect, cases have been described in breast *ese findings are corroborated by other authors, and the cancer cell lines in which increased endogenous expression same mutations have been identified in metastatic biopsies levels of HER2 V777L activated signal transduction path- of eight patients with ER + metastatic breast cancer (MBC), ways, but this did not significantly increase tumor growth as mutations that were acquired under the selective pressure of ER-directed therapy such as aromatase inhibitors [36]. [61]. *e effects of V777L seem enhanced by mutations in the PIK3CA gene given that, in the presence of mutation *e same authors demonstrated that the resistance to ER- directed therapy was overcome by combining fulvestrant PIK3CA E545K, V777L gives rise to enhanced interaction between p58 and HER3. *is suggests that reverse muta- with the irreversible HER2 kinase inhibitor neratinib. *ese tions of the HER2 gene could require other genetic alter- data suggest that the prevalence of HER2 mutations might ations to promote cellular transformation and enhance increase in metastatic ER+ breast cancer treated with anti- interactions between signaling partners [31]. *is mutation ER therapy, and these mutations are a distinct mechanism of has been associated with the intrinsic development of acquired resistance to ER-directed therapy in metastatic trastuzumab resistance [45]. Although the mutation has breast cancer that could be solved by the treatment with an irreversible HER2 inhibitor. Overall, these data suggest that been associated in some preclinical studies with a dimin- ished response to lapatinib, afatinib, and neratinib, several patients with ER+/HER2 mutations would benefit from HER2-targeted therapies in combination with hormonal studies have shown reduced tumor growth and signaling activity in tumors with the V777L mutation treated with therapy. If ongoing clinical trials confirm these results, new approaches could be adopted in order to promote a better lapatinib [44, 45]. A response has been observed to com- bined treatment with neratinib and other drugs in patients response in patients with ER + MBC, and one of these with ER + V777L breast carcinoma [35]. No cases relating strategies could be to identify HER2-mutant-resistant clones this mutation to the response to pertuzumab have been to ER-directed therapy [36]. Journal of Oncology 7 observed in cell lines overexpressing HER2 K753E. In HER2 Mutation V842I has been detected in various types of tumor tissue. *is is also an activating mutation associated K753E mutant cells resistant to lapatinib, a greater affinity of the drug for the HER2 protein was observed compared to with HER2 gene amplification and increased phosphoryla- tion of different signaling proteins [28] and also represents a wild-type cells and other variants. *is reveals that resistance hotspot in HER2 [58]. to this drug is unrelated to a lack of binding to its target [63]. *e effects of V842I on the response to anti-HER2 It has also been related to resistance to trastuzumab and therapy in patients with HER2+ breast cancer have not been appears in 2 out of every 18 patients with metastasis [32]. yet explored. Some in vitro studies indicate the resistance to While cell lines that show this mutation are resistant to trastuzumab and lapatinib of cell lines with this mutation lapatinib, they are sensitive to neratinib, which could benefit patients developing resistance to trastuzumab therapy [41]. [44]. *is mutation is the most common mutation in co- lorectal cancers, and in vitro studies have shown that this Following trastuzumab therapy, the appearance of K753E and L755S mutants could suggest their potential role mutant was not sensitive to neratinib [62]. However, given its recurrent expression in different tumor tissues and its as drivers of developing trastuzumab resistance during HER2+ tumor progression [32]. association with amplification of the gene, studies are warranted to clarify its impact on the receptor’s kinase Mutation I767M is a hotspot in gene HER2 [58] iden- activity. tified in patients with HER2+ breast cancer [54]. Its ex- *e nonsynonymous mutations D769Y and D769H are pression has been examined in vitro in HER2- among the most frequent somatic mutations of the HER2 overexpressing mammary cell lines and in HER2-negative gene. *ey are located in exon 19, at position 769 of the TK cultures. In the former cells, the presence of this mutation domain, which is important for ATP-HER2 binding [29]. along with mutations in the genes PIK3CA and TP53 conferred a significant growth benefit over cells with the Both mutations have been characterized as activators in mammary epithelium cell lines, and in vivo studies have wild-type HER2 gene. Further, both the mutant and wild- type protein featured similar AKT and MAPK signaling revealed neratinib as effective at blocking tumor growth in HER2+ breast carcinomas with these mutations [28, 42]. levels, although the AKT pathway remained active over time for longer in the cells expressing HER2 I767M [47]. In Cases have been described of xenografts acquiring the D769Y mutation following treatment with trastuzumab, vitro studies conducted by Nagano et al. [44] indicate the along with their subsequent resistance to trastuzumab and sensitivity of I767M to therapy with both TK inhibitors lapatinib, suggesting its possible role in acquired resistance (lapatinib, neratinib, and afatinib) and the monoclonal to anti-HER2 therapy [42]. In mutation D769Y, the change antibody trastuzumab. from aspartic acid to tyrosine could lead to changes in According to the data from COSMIC and cBioPortal, electrostatic interactions, due to the substitution of a neg- while other mutations in this kinase domain have been described (i.e., V797A, D808E, D873G, and M889I), there atively charged acid side chain at physiological pH with the capacity to form hydrogen bridges and bind phosphate are still no data regarding their role in HER2+ breast cancer. groups. As this mutation occurs at an important position for ATP binding to the receptor, this change could benefit this 2.3. Mutations in the Juxtamembrane Domain. *e juxta- binding and thus diminish the impacts of lapatinib and membrane domain, containing 39 amino acids (Figure 1), is neratinib therapy, whose mechanism of action is to impair involved in receptor dimerization and stability. Several this binding of ATP to HER2 [42]. *e D769Y mutation authors have described reoccurring mutations in this do- promotes the phosphorylation of HER2, EGFR, HER3, and main with a functional activating effect in different cancer ERK and transformation of mammary epithelial cells. Cell types [10]. However, these studies do not specify if these lines with this mutation display sensitivity to neratinib, in mutations occur in patients with HER2-positive breast smaller measure to lapatinib and resistance to trastuzumab cancer. In our search of mutations in the COSMIC and [42], although Nagano et al. recently described sensitivity to cBioPortal databases, we found two mutations, R678Q and lapatinib and afatinib in in vitro studies [44]. Some authors V697L, present in HER2-positive breast carcinoma. In vitro report that loss of the acid side chain or addition of an studies indicate that R678Q is an activating mutation that aromatic ring to amino acid 769 could increase HER2’s TK confers sensitivity towards treatment with trastuzumab, activity due to dimeric interactions between the kinase lapatinib, afatinib, and neratinib (Table 2) [10, 33, 44] and domains of HER2 and HER3. Mutations D769H/Y may has been classified as a hotspot [64]. No functional data exist enhance hydrophobic contacts and heterodimerization of for mutation V697L, but it has been described as a muta- HER2. Besides, the D769H alteration could lead to activation tional hotspot and data available for other cancer types within the HER2 monomer, adding hydrogen bonds to its suggest its oncogenic effect. own activation A-loop [46, 54]. Mutation K753E leads to a shift in charge of the amino 2.4. Mutations in the Transmembrane Domain. *e trans- acid’s side chain, which goes from being basic to acidic, thus possibly affecting the electrostatic interactions of the protein. membrane domain of receptor HER2 (aa 649–675, Figure 1) plays an active role in its dimerization with the consequent Several authors have related this mutation with lapatinib resistance, and this could be attributed to its close proximity activation of kinase activity and promotion of the signaling with the L755S mutation which confers resistance to this pathways responsible for tumor cell growth. Recently, re- drug [32, 41]. Recently, the effect of this mutation has been current mutations have been identified with an activating 8 Journal of Oncology dimerization of the receptor, kinase activation, and malig- effect in different cancers [10]. However, the data sources COSMIC and cBioPortal reveal that no mutations in this nant cell transformation. Both mutations appear to have a homologous effect. Of the two, S310F has been most studied domain occur in HER2-positive breast cancer. In the present study, we identified only one mutation, I655V (Table 2), in in different tumor tissues (both HER2-positive breast and HER2-positive patients, which, according to Fleishman et al. HER2-negative lobular breast, lung, colorectal, ovarian, [65], involves an altered receptor conformation that renders bladder, micropapillary urothelial, and endometrial) it a constitutively activated state, promoting the homo- [29, 33, 54, 68–70] while S310Y has been more commonly dimerization and autophosphorylation of HER2 and acti- associated with pulmonary adenocarcinoma while it has vation of the TK domain [65]. Singla et al. [49] found, among been also found in HER2-positive and HER2-negative breast cancer [29, 33, 55, 71]. *e fact that mutations in this po- patients in Indian hospitals, a positive significant association between HER2 I655V and the susceptibility of developing sition are present in different cancers suggests it could be an oncogenic mutation [72]. *ey are therefore mutations that breast cancer, while other authors have detected negative correlation when examining patients in Brazil [66]. A meta- activate HER2 protein via elevated phosphorylation of the C-terminal tail, as is the case of mutation S310F/Y, or in- analysis conducted in 2019 [67] revealed the impacts of ethnicity on the association between mutation HER2 I655V ducing covalent dimerization sustained by intermolecular and breast cancer risk, observing positive correlation in Asia disulfide bridges [73], as in the case of mutations G309E/A, and Africa but not the other continents. only described in HER2-negative breast cancer and other *e relationship between this mutation and the response cancers [28, 73]. In the presence of an S310F/Y mutation, it to trastuzumab-containing chemotherapy in HER2-positive has been noted that protein HER2 seems more sensitive to breast cancer patients has been examined, yet results have anti-HER2 therapy containing neratinib and possibly tras- tuzumab in patients with HER2+ breast cancer [33, 54, 55]. been contradictory. In some studies, disease-free survival (DFS) and delayed DFS (DDFS) were improved in patients Accordingly, in cells featuring ECD mutations, trastuzumab may bind to this region and prevent homodimerization and with this mutation and the genotypes HER2 Val/Val or Val/ Ile compared to the genotype Ile/Ile [48]. On the contrary, activation of the receptor. However, because of the constant activation of the TKD in tumors with mutations at this Furrer et al. [52] noted a worse response to trastuzumab- containing chemotherapy, while other studies have found no domain, the antiproliferative effects of monoclonal anti- correlation [49–51]. *ese results preclude establishing a bodies may be limited despite inhibiting dimerization [74]. clear relationship between this polymorphism and the de- *e effects of these mutations on the response to pertu- velopment of resistance to treatment with trastuzumab. *e zumab and trastuzumab have been investigated recently effect of trastuzumab and other antibodies may be limited in using in vitro 5637 culture cells and single-molecule in- tumors that show mutations in the TMD, as HER2 di- teraction analyses using TIRF microscopy [74]. *e overexpressed S310F as well as G309A, G309E, and S310Y merization seems stable despite trastuzumab binding to its extracellular domain. Neratinib, which binds to the HER2 HER2 mutants reacted to trastuzumab, but S310F mutant did not react to pertuzumab along with S310Y or G309E receptor’s kinase domain and inhibits its phosphorylation and activity, can exert antitumor effects irrespective of the mutants. *ereafter, authors tested the effects of trastu- domain affected by mutations and has an impact on this zumab and pertuzumab using both wild-type HER2 and HER2 I655V mutation in different lung cancer cell lines [68]. S310F mutant. In this case, trastuzumab did not inhibit the Something similar occurs with the risk of cardiotoxicity activation of the HER2 receptor, suggesting that the S310F induced by trastuzumab. Despite initial proposals that being HER2 mutant did not form homodimers or heterodimers a carrier of the mutant allele, genotypes HER2 Val/Val or with wild-type HER2. Because pertuzumab did not inhibit Val/Ile, was a possible predictor of this adverse effect of the the phosphorylation of HER2 while it bound to wild-type drug [50], this relation could not be later confirmed [53]. HER2, EGFR-mediated phosphorylation is expected to occur on the S310F mutant; therefore, trastuzumab in Some authors have suggested that carrying this mutation only affects the survival of patients with breast cancer who combination with pertuzumab is not effective [74]. *is residue is located close to one of the key residues, K311, for overexpress the HER2 gene [48]. To date, the possible effect of this mutation on the actions of other HER2-target drugs receptor-antibody binding whose replacement with ala- such as pertuzumab, neratinib, afatinib, or lapatinib has not nine, via targeted mutagenesis, leads to a drastic reduction been addressed. in the response to this drug in cells expressing the muta- tion. Amino acid substitutions in these residues could provoke changes in electrostatic interactions or even give 2.5. Mutationsin theExtracellularDomain. *e extracellular rise to a stearic impediment possibly affecting pertuzumab domain is composed of four subdomains involved in di- binding to the HER2 receptor [69]. merization of the receptor and thus in its activation. Several Other less frequent mutations in the ECD have been described, such as R190Q, P523S, and Q548R, in patients mutations in the ECD domain have been described in pa- tients with HER2-positive breast cancer both in PubMed and with breast cancer without specifying HER2 amplification, in which no relationship has been found between the mu- the databases COSMIC and cBioPortal, as described below. *e most common mutations in the ECD of the HER2 tations and prognosis [75]. Even rarer are L313I and R456C, receptor, S310F and S310Y, corresponding to the gene observed in two patients with HER2+ breast cancer effec- hotspot (Table 2) [64], have been related to the increased tively treated with neratinib [42]. Journal of Oncology 9 data available for HER2-negative breast cancer patients *e COSMIC and cBioPortal databases also describe other mutations in this domain about which there are no (Table 3), functional activating HER2 mutations, V777L, L755S, S310F, D769H/Y, and V842I, may similarly confer published data for HER2-positive breast cancer: A37T, P232S, D277H (also described in bladder cancer, enhances sensitivity to HER2-directed pharmacological products. its activation together with S310F, de Martino et al. [76]), Furthermore, a high number of HER2-mutant tumors are T297I, E405D, and H470Q. also ER+, and as discussed before, the most effective treatment will be combining fulvestrant with the irreversible inhibitor neratinib [21, 35]. Overall, HER2-negative breast 2.6. Beyond HER2+ Breast Cancer: Lessons from Clinical cancer patients carrying the above mutations can benefit Data from the Use of HER2-Directed ?erapy against HER2 from HER2-targeted therapy; this is in agreement with data Mutant Cancers. Around sixteen clinical trials investigating previously published by other authors [32, 78]. the efficacy of HER2-directed therapy in HER2 mutant cancers are currently active [21]. Four phase II studies are studying the efficacy of different pharmacological products 2.7. Conclusions and Future Perspectives. Research and (afatinib, neratinib plus trastuzumab, poziotinib, and clinical studies have shown that HER2 overexpression/ pyrotinib) in different types of metastatic HER2 non- amplification is associated with poor survival in breast amplified but with HER2 mutant breast cancer. *ere are a cancer patients. Further, in vitro and in vivo studies indicate relatively large number of pharmacological approaches for that the presence of somatic HER2 mutations could influ- breast cancer carrying HER2 mutants. In part, we have ence the clinical outcome of HER2-positive patients under reached this situation because activating mutations for currently approved treatments (Table 1). New findings in HER2 have been shown to be largely dependent on tumor breast cancer cells suggest that HER2 could interact phys- ically with PMCA2 and the cannabinoid receptor CB histology and have shown different clinical responses. Some R. mutations are sensitive in a specific type of cancer and in Hence, targeting these heteromers could be a new thera- others could be associated with resistance, suggesting that peutic option and prognostic tool in HER2-positive breast there may be other mechanisms specific with the tumor that cancer. Recently, in vitro and in vivo studies in metastatic requires further research. ER + tumors suggest that some HER2 mutations emerge as a *e focus of this review is to assess the possible clinical mechanism of acquired resistance to endocrine therapy implications of HER2 mutations in HER2-positive breast opening new options of treatments in patients with cancer patients; in this study, we have described that the ER + MBC. most prevalent mutations found in HER2 gene in HER2- In this review, we identify the more prevalent somatic positive breast cancer (Table 2) are present also in HER2- HER2 SNP mutations appearing in HER2-positive breast negative breast cancer [28, 29, 32, 34, 57]. We would like to cancer patients and summarize their possible implications address, using clinical data available, if HER2-negative pa- for current HER2-targeted therapy (Figure 4). We found tients with HER2 somatic mutations are potentially good that somatic HER2 mutations occur in low frequency in candidates for HER2-directed therapy. *e clinical data HER2-positive breast cancer patients. In total, 11 somatic available have been reviewed by Cocco et al. [21] and are mutations have been identified, and according to infor- summarized in Table 3. *e first patient diagnosed with mation available from in vitro and in vivo studies, 9/11 are triple-negative breast cancer, carrying two HER mutations classified as oncogenic and hotspot (see Table 2), and several (V777L and S310F), respond to lapatinib and trastuzumab- authors have identified the presence of these mutations also based therapies during 6 months. A second case diagnosed in HER2-negative breast cancer patients. For two mutations, with ER + HER-negative breast cancer, carrying a HER2 I767M and K753E, there is insufficient information so far to S310F mutation, was treated during 12 months with the classify them as oncogenic and/or hotspot. In HER2-positive combination of trastuzumab, pertuzumab, and fulvestrant. tumors, the TKD harbored the higher number of somatic An additional case with ER+, HER2-negative metastatic mutations (7/11), contrasting with the low number of breast cancer with HER L755S mutation was treated with mutations found in the extracellular and transmembrane neratinib monotherapy experiencing improvement in domains. *e relevance of some mutations identified in this symptoms and tumor markers. Another case described a study requires further investigation. HER2 (D769H) mutant with metastatic HER2-negative For the reviewed somatic HER2 mutations, no sensitivity breast who achieved a partial response with trastuzumab, or resistance data are available for pertuzumab, with the pertuzumab, and chemotherapy (Table 3). *ese clinical data exception of mutation D769H. For some mutations, avail- are in agreement with the pharmacological profile of the able data are inconclusive requiring more functional studies. SNPs of HER2 reviewed in this study (Figure 3). In the phase HER2-positive patients carrying S310F, S310Y, R678Q, II MutHER trial, the activity of neratinib in HER2 mutant D769H, I767M, or V777L emerged as potentially good nonamplified metastatic breast cancer was investigated candidates for HER2-targeted therapy and could have a (Table 3); the patients obtained clinical benefit over 24 favorable outcome because of sensitivity to current phar- months [77]. A case report was a HER2-negative breast macological treatments with the exception of inconclusive cancer patient with two detected mutations in ERBB2 (S310F data for the impacts of trastuzumab in V777L (Figure 3). and D769Y mutations) who benefited from lapatinib Patients with L755S or D769Y might also benefit from combined with endocrine therapies [78]. Based on clinical neratinib or afatinib treatment. In contrast, patients with the 10 Journal of Oncology Table 3: Clinical response of HER2 mutant breast tumors to anti-HER2-based therapy. No. Type of breast cancer HER2 mutation Pharmacological treatment Outcome Reference patients V777L Improvement during 6 Reviewed in 1 Triple-negative Lapatinib, trastuzumab S310F months 21 Trastuzumab, pertuzumab Improvement during 12 Reviewed in 1 ER+/HER-negative S310F fulvestrant months 21 Improvement during 12 Reviewed in 1 ER+/HER-negative L755S Neratinib months 21 Metastatic HER2- Trastuzumab, pertuzumab Reviewed in 1 D769H Partial response negative chemotherapy 21 1 HER2-negative S310F/V842I Neratinib Benefit [77] 6 HER2-negative L755S Neratinib Benefit [77] 1 HER2-negative D769H Neratinib Benefit [77] 1 HER2-negative p.L755_T759del Afatinib, trastuzumab Response [78] 1 HER2-negative S310F and D769Y Lapatinib and endocrine therapy Response [78] Juxtamembrane Transmembrane Extracellular Tyrosine kinase domain domain domain domain L755S V777L D769Y D769H I767M V842I K753E R678Q I655V S310F/S310Y Trastuzumab Pertuzumab Lapatinib Neratinib Afatinib Resistant Inconclusive Sensitive No data Figure 3: Pharmacological impacts of the SNPs reviewed in this study. *e sensitivity of HER2 mutants to different drugs used as anti-HER2 therapy is shown. *e pharmacological products have different levels of activity against mutant HER2+ proteins in vitro. When data from in vivo studies (xenotransplant and/or breast cancer patients) were available, they were considered for the analysis. Furthermore, some mutants that have been described to be sensitive to specific inhibitors in preclinical analyses were instead found to be resistant to the same drugs; in this case, we have indicated this information as inconclusive data. L755S V777L I767M D769Y/H S310F/Y K753E R678Q V842I I655V III III IV TMD JMD TKD 0 200 400 600 800 1000 1250 aa Figure 4: Schematic diagram of HER2 protein with the locations of the SNPs reviewed in this study found in HER2-positive breast cancer patients. Domains I, II, III, and IV belong to the extracellular domain (ECD); TMD: transmembrane domain; JMD: juxtamembrane domain; TKD: tyrosine kinase domain. Journal of Oncology 11 [10] K. B. Pahuja, T. T. Nguyen, B. S. 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Published: Mar 7, 2020

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