Narrative review on the evolving role of HER2/neu targeting in uterine serous cancers

Introduction

Background

Endometrial cancer (EC) is one of the most common cancers affecting women worldwide. In the year 2020, there were over 417,000 new cases of EC and 97,000 deaths globally (1). Uterine serous cancer (USC) is an aggressive histological subtype of EC which accounts for 39% of all deaths due to EC despite constituting only 10% of all ECs in incidence (2). Historically, EC was categorised in to two groups: type I which are predominantly low-grade endometroid tumors and type II consisting of USC, clear cell carcinoma, carcinosarcoma and grade 3 endometroid tumors (3). Similar to endometroid EC, USC usually presents with postmenopausal bleeding but often arises from an endometrial polyp on a background of atrophic endometrium (4). In apparently early-stage disease, there is a tendency for lympho-vascular space invasion (LVSI), lymph node involvement and intra-peritoneal spread despite minimal or no myometrial invasion. All stage 5-year overall survival (OS) of USC is much lower than endometroid EC at 52% vs. 83% respectively (5). Therefore, in contrast to endometroid EC which has an excellent prognosis at early stages of the disease, USC is a high-grade tumor with high recurrence rates and poorer prognosis (6,7).

USC has been associated with increasing age, women of black ethnicity, history of breast cancer and tamoxifen use (8). Contrary to previous data, obesity is reported to be a risk factor for USC although it appears to be hormone independent (8,9). Population studies on EC have demonstrated racial disparities in the incidence, management and outcomes of women affected by the disease. Data suggest that black women are at increased risk of non-endometroid tumors including USC, present at advanced stages and have lower OS rates in comparison with white women (10,11).

Objective

In the recent years, the HER2/neu pathway has emerged as a commonly affected molecular aberration in USCs that contributes to their aggressive nature. Biomarker testing guidelines have not yet been defined for such tumors and the efficacy of HER2/neu targeting agents have been uncertain. The main objective of this article is to review the evidence regarding testing and reporting of HER2/neu amplification/overexpression in USCs and define the role of HER2/neu targeting agents in these cases. We focus on the methods of testing and interpreting HER2/neu overexpression/amplification in USCs. A summary of various preclinical and clinical trials available for HER2/neu targeting agents in USCs, the efficacy of such therapeutic targeting, emerging therapies and future directions have been outlined. We present this article in accordance with the Narrative Review reporting checklist (available at https://atm.amegroups.com/article/view/10.21037/atm-23-1465/rc).

Methods

PubMed/Medline database was searched for articles on HER2/neu testing and targeting in USCs from inception to 28^th February 2023. The search terms used were “HER2”, “HER2/neu”, “Her2neu”, “uterine serous cancer”, “uterine papillary serous cancer”, “serous endometrial cancer”, “trastuzumab”, “pertuzumab”, “T-DM1” and “trastuzumab emtansine” (Table 1). Backward and forward reference searching was done on retrieved articles to include any articles which answer the study objectives. Results and references of interim study reports were updated after the date of the initial search when full results were published. The retrieved articles were analysed and summarized in the review (Figure 1).

Figure 1 Literature search strategy. HER2, human epidermal growth factor receptor 2; T-DM1, trastuzumab emtansine.

Discussion

Molecular profile and classification

USCs demonstrate the typical histological features of serous differentiation, papillary architecture, nuclear atypia and pleomorphism, slit-like spaces, scanty cytoplasm and psammoma bodies in one-third of cases (12,13). Historically, the Bokhman’s binary system was used to classify ECs into type I and type II tumors with distinct clinical, pathological and prognostic indicators. The Cancer Genome Atlas (TCGA) classification system categorises EC into four groups: (I) POLE ultra-mutated EC; (II) microsatellite instability hypermutated EC due to dysfunctional DNA mismatch repair proteins; (III) copy number low/microsatellite stable EC which are mostly endometroid (49%); (IV) copy number high with TP53 mutations in >90% and include USC (14). In the study by the TCGA Network, 50 of the 53 (94%) serous tumors analysed were classified under the cluster 4 (copy number high) group and had significantly recurring amplifications of HER2/neu oncogene. This group was also associated with significantly worse progression-free survival (PFS) compared to the endometrioid clusters and was suggested as a potential therapeutic target (15). Several other studies have shown a strong correlation between TP53 mutation and HER2/neu expression and/or amplification in ECs (16,17). Other gene mutations identified in USC include PIK3CA, PPP2R1A, ERBB2 (also known as HER2 and HER2/neu) and CHD4 (12,15,18).

HER2/neu receptor in USC

HER2/neu receptor is a 185-kDa, 1,225-aminoacid transmembrane glycoprotein tyrosine kinase receptor belonging to the epidermal growth factor receptor (EGFR) family encoded on the ErbB-2 gene found on the long arm of chromosome 17 and is also known as Erb-b2, ERBB2, c-erbB-2 or p185^HER2. It consists of an extracellular domain which binds with other members of the EGFR family, a membrane spanning hydrophobic transmembrane domain and an intracellular domain responsible for the kinase action (19). HER2/neu receptor is an orphan receptor as it does not have a direct ligand. Instead, it binds with the extracellular domain to other EGFR family ligands activated by EGF ligand interaction. Such homo- or hetero-dimerization leads to activation of the intracellular tyrosine kinase function by autophosphorylation which in turn leads to activation of downstream signaling molecules and results in growth and proliferation. The various downstream pathways that are activated by HER2/neu receptor activation includes Ras/Raf/mitogen-activated protein (MAP) kinase, the PI3K/Akt, and the phospholipase C_γ (PLC_γ)/protein kinase C (PKC) pathways. In malignant cells, activation of these mitogenic cell signaling pathways leads to proliferation, invasion, angiogenesis, migration and cell survival (20). HER2/neu mediated tumorigenesis can occur due to overexpression of the proto-oncogene coding for HER2/neu receptor or by overactivation of the receptor, though the former appears to be the most common case in clinical studies (19).

Non oncogenic activity of the HER2/neu receptors is important for the development of organs such as skin, breast, gastrointestinal, reproductive and urinary tracts (21). HER2/neu receptor overexpression has been described in tumorigenesis of a number of cancers including breast, gastric, ovary and uterine serous carcinoma (22,23). In USC, overexpression and/or amplification of HER2/neu by immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) respectively ranges from 16–48% (24-28). HER2/neu positive tumors were associated with advanced disease, myometrial invasion (24,25), lymphovascular space invasion (LVSI) (25,26), higher recurrence rates (24,26), as well as poorer overall and disease-free survival (24-28). In essence, the presence of the HER2/neu oncogene confers a more biologically aggressive disease with poorer prognosis.

There also appears to be a trend towards higher expression and amplification of HER2/neu in black women. Retrospective single centre studies by Santin et al. and Morrison et al. reported HER2/neu amplification in black women in the range of 18–67% (27,29). Similarly, overexpression of HER2/neu in black women ranges from 33–90% in comparison to 13–48% in white women (29,30). These findings have also been correlated with poorer survival in both studies. Further analysis of intensity of IHC staining revealed that heavy (3+) IHC staining in keeping with HER2/neu overexpression was increased in black women and appears to be the strongest prognostic factor for shorter survival (30).

HER2/neu testing and reporting in USC

HER2/neu testing in patients with USC is of paramount importance, as therapeutic decisions and prognostication depends on the accuracy of testing. The criteria for testing in USC were derived from pre-existing standardised protocols for testing in breast and gastric cancers (31-33). HER2/neu protein overexpression on IHC and amplification by FISH or chromogenic in situ hybridization (CISH) have been described in the literature to define HER2/neu positivity in tumor (34-36) (Table 2).

HER2/neu overexpression

Correlation between HER2/neu overexpression, IHC scoring systems and clinical performance have not been satisfactorily elucidated in women with serous ECs. Data on HER2/neu expression from breast cancer cells cannot be extrapolated for USC as it has been widely recognised now that the staining pattern and expression are different for different organs (46). The expression and amplification of HER2/neu differs between tumors of different organs so does the pattern of staining observed in breast, gastric and USC (33). HER2/neu positive breast tumors usually demonstrate a relatively uniform and circumferential staining on IHC while lateral or basolateral, i.e., ‘U-shaped’ staining is seen more frequently in gastric and USC (31). In addition, tumors with basolateral/lateral membranous staining as seen in gastric and serous ECs demonstrated a glandular or pseudo-glandular pattern. Recognition of these differences is important when applying existing guidelines for breast and gastric cancer to HER2/neu testing in USC and highlights the need for testing guidelines specific to EC. Previous studies evaluating HER2/neu expression in endometrial tumors have used the IHC scoring definition of 3+ if >10% cells in the tumor have shown strong complete membrane staining to define HER2/neu positive cells (24,30,38,40,47). Recent studies have found that using a scoring criterion of >30% cells showing strong complete membrane staining to define HER2/neu positive tumors to be more concordant with clinical behaviour (43). Another issue to consider is whether to consider 2+ IHC scoring tumors as HER2/neu positive or equivocal. Though the initial GOG trials have considered such tumors to be HER2/neu positive (38,40), the eligibility as HER2/neu positive tumor in the recent trial by Fader et al. necessitates all 2+ IHC scoring tumors to be confirmed with FISH for gene amplification. The criteria employed defined a specific group with HER2/neu positive tumors who derived significant clinical benefit from targeted therapy as demonstrated even in the subsequent OS results (43,48).

HER2/neu amplification

Amplification by FISH is expressed as the ratio of HER2/neu to chromosome enumeration probe 17 (HER2/neu:CEP17) and HER2/neu copy number signal per cell (49). The International Society of Gynecological Pathologists (ISGyP) published practical recommendations allowing tumors with an IHC score of 2+ with FISH HER2/neu:CEP17 ratio ≥2.0 or <2.0 with average HER2/neu copy number ≥6/nucleus to be designated as HER2/neu positive tumors, in addition to those scoring 3+ on IHC. While definite testing guidelines are yet to be established, these criteria could form the basis for future guideline development for EC (46).

Challenges in HER2/neu testing for USC

Concordance between the two testing modalities has also been an important subject area of previous studies. Reported concordance rates between IHC and FISH/CISH in USC differ significantly with estimated rates between 32% and 100% (35,36). The highest concordance was observed in tissues staining 3+ on IHC (35). It is important to note however that testing methods and scoring criteria do vary between studies and could have contributed to the differences reported. Buza et al. showed that the concordance between HER2/neu overexpression and amplification was 75% when Food and Drug Administration (FDA) criteria for breast cancer was used for IHC scoring while the concordance increased to 81% when American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) scoring system for breast cancer was used (31). Another challenge encountered with HER2/neu testing in USC is intra-tumoral heterogeneity which is described as the presence of at least 2 degrees of difference in staining in at least 5% of tumor cells or amplification of HER2/neu within the same tissue sample (50). Intra-tumoral heterogeneity ranging from 31–97% in HER2/neu expression has been reported with IHC (31,32,36). In small samples, this could be misleading as results may not be entirely representative of the whole tumor and potentially risks excluding some patients from targeted therapy. Therefore, testing multiple sections or larger area of tissue is recommended to reduce the occurrence of false results (31,32,42).

Novel methods of testing HER2/neu

Next-generation sequencing (NGS) is a novel technology used in the identification of gene mutations in cancers and provides a molecular basis for targeted therapy. NGS isolates nucleic acid (DNA or RNA) from the tumor sample, generates sequencing libraries prior to amplification of DNA and subsequently analyses the data (51). A comparative study of targeted NGS with IHC and FISH for the ErbB2 gene in USC showed that NGS was comparable to IHC and FISH in detecting ErbB2 gene amplification with 100% concordance (52). Although the results of this study were positive, it had a small sample size and did not demonstrate the superiority of NGS over current testing modalities.

In breast cancer, alternative HER2/neu testing techniques like immunodetection using Phosphor Integrate Dot fluorescent nanoparticles (53), novel gene protein (54) and the HER2DX clinical response prediction assays (55) have been reported. Hou et al. used the novel gene protein assay on double equivocal cases (IHC and FISH) to determine both gene copy number and protein expression simultaneously and also identified HER2/neu heterogeneity in breast cancer cells (54). This is a promising finding but requires further clinical testing in other tumors including EC. Larger studies are required to confirm the results and cost effectiveness of adopting alternative testing techniques including targeted NGS in clinical practice in comparison with IHC and FISH.

Targeting HER2/neu in uterine serous papillary cancers

Various pharmacologic agents have been developed to inhibit the activity of HER2/neu receptor in breast cancer cell lines with improvement in survival outcomes. Given the molecular similarities of USC with breast cancer, these agents are being actively investigated in EC in preclinical and clinical settings with considerable success.

They can be grouped as follows:

Agents with demonstrable activity in clinical studies:

• Trastuzumab.

Agents with demonstrable activity in preclinical studies:

• Targeting extracellular domain of HER2/neu receptors: pertuzumab;
• Antibody drug conjugates (ADCs): trastuzumab emtansine (T-DM1), DHES0815A, SYD985 (Byondis B.V., Nijmegen, the Netherlands);
• Targeting intracellular domain of HER2/neu receptors: afatinib, neratinib, dacomitinib, lapatinib;
• Targeting the downstream pathway of HER2/neu receptor activation such as PIK3CA/Akt/mTOR signaling pathways: GDC-0980 (Genentech Inc., South San Francisco, CA, USA), taselisib.

The only drug tested and used in current clinical practice is trastuzumab, while the other HER2/neu targeting agents were tested in preclinical trials on cell lines. Though promising, the clinical efficacy of these drugs is yet to be established in real world settings.

Trastuzumab

The most important and well-studied of these drugs is trastuzumab (Herceptin, Genentech, San Francisco, CA, USA/Hoffman-Roche, Switzerland). Trastuzumab is a humanized murine IgG1 immunoglobulin that targets the extracellular domain IV of HER2/neu and interferes with dimerization leading to suppression of downstream signaling pathways (56). It also acts by reducing HER2/neu activity by inducing receptor degradation through the ubiquitin proteosome pathway (57). Binding of trastuzumab to HER2/neu receptor also activates immune recognition of tumor cells via antibody dependent cellular cytotoxicity (ADCC) (56). As early as 2002, Santin et al. proposed that trastuzumab can be a potential therapeutic option targeting HER2/neu overexpressing USC. They made this proposition on the basis of their finding that cell lines from patients with chemotherapy and radiotherapy resistant USC were highly sensitive to trastuzumab mediated ADCC (58). In 2006, Jewell et al. reported the successful use of trastuzumab in achieving a partial response on two subsequent recurrences in a patient with HER2/neu overexpressing stage IIIA endometrioid EC (59). Villella et al. reported two patients with HER2/neu positive advanced USC (stage IIIC & IVB) who achieved stable disease and complete response with trastuzumab, respectively (37).

The GOG 181B trial was a phase II trial conducted to evaluate the efficacy of single agent trastuzumab in HER2/neu positive advanced/recurrent endometrial carcinoma. The trial initially recruited patients who were considered HER2/neu positive based on IHC results alone (2+/3+ overexpressing tumors) from 2000 to November 2002. But when 23 patients (Sample A) included during this time (Period A) showed no response, the trial was modified to include patients who were FISH positive for HER2/neu amplification between 2004 and 2007 (Period B). Sample B included patients who showed HER2/neu amplification in Period B plus patients who were FISH positive amongst Sample A. Despite these amendments, the study did not show major objective tumor responses amongst its participants. Tumor response and survival was not associated with HER2/neu amplification or overexpression. The authors concluded that trastuzumab has no activity in HER2/neu positive EC, though the study closed before completion due to poor accrual (40).

A phase II randomized controlled trial by Fader et al. evaluated the addition of trastuzumab to conventional chemotherapy in 58 evaluable patients with advanced and recurrent USC. The experimental arm received paclitaxel and carboplatin for 6 cycles with trastuzumab followed by trastuzumab maintenance till disease progression or toxicity. The trastuzumab arm experienced significant increase in median PFS [12.9 vs. 8.0 months, hazard ratio (HR) =0.46, P=0.005] and OS (29.6 vs. 24.4 months, HR =0.58, P=0.046) compared to the control arm. The greatest benefit was observed in the subset of women who received trastuzumab as primary treatment (OS: not reached vs. 24.4 months, HR =0.49, P=0.041; PFS: 17.7 vs. 9.3 months, HR =0.44, P=0.015) (43,48). As a result of these encouraging results, National Comprehensive Cancer Network (NCCN) guidelines have incorporated trastuzumab to conventional chemotherapy as primary treatment for advanced stage USC and as a first-line option for recurrent USC (60). A modelling study based on a theoretical cohort of 4,000 women also showed that addition of trastuzumab to conventional chemotherapy is cost-effective in advanced and recurrent USC until the cost of treatment for 6 months crosses $38,505 (61). Trastuzumab has good tolerability and an acceptable toxicity profile when given in patients with USC. The most common side effects are gastrointestinal of which almost 95% are low grade. No significant toxicity was observed between experimental arm including trastuzumab and control arms, even in cardiac toxicity (62). Table 3 shows summary of clinical trials evaluating USC treated with the HER2/neu targeting agent trastuzumab.

In stage I serous ECs, conventional staging surgery and chemotherapy seems inadequate as the observed recurrence rate is 25.4% despite 71% of patients receiving some form of chemoradiation. Almost 26% of this cohort show HER2/neu positivity and are associated with poorer overall [adjusted R (aHR) =2.00, 95% confidence interval (CI): 1.04–3.88, P=0.039] and PFS (aHR =3.50, 95% CI: 1.84–6.67, P<0.001) compared to HER2/neu negative tumors (26). Clinical trials targeting HER2/neu in this early-stage USCs of patients are lacking (66).

Pertuzumab

Pertuzumab is another humanized monoclonal antibody that targets extracellular domain IV of HER2/neu receptor, which is a different epitope than that targeted by trastuzumab. This binding of pertuzumab to HER2/neu receptor inhibits heterodimerization of HER2 and HER3 which is considered the most potent cellular signaling heterodimer of the EGFR family (67). Pertuzumab works predominantly by stimulating immune activation by ADCC. Pertuzumab has been shown to have efficacy similar to trastuzumab in HER2/neu overexpressing USC cells in vitro. Interestingly, it has also been shown that addition of pertuzumab to trastuzumab significantly increased the ADCC dependent cell killing in vitro in USC cells with low or no expression of HER2/neu receptors compared to either drug alone (68).

T-DM1

T-DM1 is an antibody-drug conjugate of trastuzumab linked to the anti-microtubule cytotoxic agent DM1 through a nonreducible thioether linkage. Each molecule of trastuzumab carries 3.5 molecules of DM1. When trastuzumab binds to HER2/neu receptors, the T-DM1 antibody-drug complex enters the cell via a receptor-mediated endocytosis. Upon proteolytic degradation, the DM1 molecules are released intracellularly and exert their antimicrotubular activities. English et al. showed that T-DM1 was more effective in vitro by inhibition of cell proliferation and induction of apoptosis in HER2/neu positive USC cell lines and in vivo by decreasing tumor formation and prolonging survival of severe combined immunodeficient (SCID) mice harbouring USC xenografts (69).

DHES0815A

DHES0815A is also an ADC in which the antibody against HER2/neu receptor named MHES0488A is bound to pyrrolo[2,1-c][1,4] benzodiazepine monoamide (PBD-MA) which is an alkylating agent at a drug antibody ratio (DAR) of 2. DHES0815A significantly decreases growth of HER2/neu overexpressing USC cell lines in an in vitro study (44).

SYD985

SYD985 is a new antibody-drug conjugate in which trastuzumab is linked to duocarmycin, a DNA alkylating agent having an average DAR of 2.8. In USC cell lines, SYD985 was shown to be 10 to 70 times more potent than T-DM1 and was also effective in USC cells with low to moderate HER2/neu expression, unlike T-DM1 which was only effective against USC with strong HER2/neu expression (70).

Afatinib

Afatinib (BIBW-2992) is an oral HER2/neu inhibiting antibody that works by targeting the intracellular tyrosine kinase domains of ErbB1, ErbB2 and ErbB4 and inhibits transphosphorylation of ErbB3. Afatinib was shown to be active in vitro and in vivo in chemotherapy resistant USC harbouring HER2/neu gene amplification (71).

Neratinib

Neratinib (HKI 272) is another tyrosine kinase inhibitor that binds to the adenosine triphosphate (ATP) pocket of ErbB1 and HER2/neu, thereby inhibiting the downstream signaling pathway. Schwab et al. showed that USC lines with HER2/neu amplification were more sensitive to growth inhibition by neratinib compared to non-amplified cell lines. Neratinib also showed in vitro activity by increasing OS and decreasing tumor growth (72). Olaparib and neratinib showed synergistic activity in USC with high HER2/neu expression. Olaparib treatment increased HER2/neu expression in USC cell lines while treatment with neratinib increased poly(ADP-ribose) polymerases (PARP) activity (73).

Dacomitinib

Dacomitinib is an oral small molecule inhibitor that acts by inhibiting the tyrosine kinase activity of HER1, HER2 and HER4. Dacomitinib has shown to significantly inhibit growth of USC lines harbouring HER2/neu amplification in a dose dependent manner (74).

Lapatinib

Lapatinib is a dual ErbB1/HER2/neu tyrosine inhibitor molecule which has shown antitumor activity in combination with trastuzumab in HER2/neu amplified USC which were impervious to trastuzumab alone in vitro and in vivo (75).

GDC-0980

GDC-0980 is a small molecule inhibitor which selectively inhibits class 1 PIK3 and mTORC1/mTORC2 kinase. PIK3/Akt/mTOR pathway is a signaling cascade that is located downstream to HER2/neu receptor activation. GDC-0980 was found to inhibit growth in USC harbouring HER2/neu amplifications. Among HER2/neu amplified USC lines, those lines that also harboured PIK3CA mutations were more sensitive to inhibition by GDC-0980 compared to PIK3CA wild type USC cell lines (76).

Taselisib

Taselisib, otherwise known as GDC-0032, is an oral small molecule inhibitor of PIK3CA. A strong differential growth inhibition was seen with taselisib in HER2/neu FISH positive tumors with PIK3CA mutation compared to those without HER2/neu amplification or PIK3CA mutation. In vivo survival benefits were observed in HER2/neu FISH positive/PIK3CA-mutated xenografts treated with taselisib compared to controls (77).

The pre-clinical evidence for HER2/neu targeting agents in USC cell lines is summarized in Table 4.

Mechanisms of resistance to HER2/neu targeted therapy in USC and ways to overcome it

Solid tumors that express HER2/neu may not respond to HER2/neu targeting therapy either from the initiation of therapy (primary resistance) or after some time of response (secondary resistance). Several factors have been proposed to account for such resistance.

Presence of p95HER2 variant

P95HER2 is a variant of HER2/neu receptor which loses the extracellular binding site for trastuzumab while retaining the intracellular domain responsible for activation of downstream signaling pathway. As a result, these HER2/neu overexpressing tumors are resistant to the effects of trastuzumab. Growdon et al. showed that almost 53% of high-grade ECs (predominantly consisting of USC) showed p95HER2 expression. This was considerably higher than p95HER2 expression in a matched breast cancer cohort (78).

Upregulation of downstream pathways

Tumors that show increased activity/signaling of HER2/neu downstream pathways such as PIK3CA and mTOR pathways are resistant to HER2/neu targeting agents. Black et al. showed that HER2/neu amplified/PIK3CA-mutated tumors were more resistant to trastuzumab compared to HER2/neu amplified/PIK3CA wild type cell lines. Resistance of tumors to trastuzumab that were transfected with oncogenic PIK3CA mutations increased compared to baseline (79).

Signaling from other HER receptors

Tumors may escape HER2/neu receptor targeting by increasing activation of other HER receptors like HER3. HER2-HER3 receptor signaling is considered the most potent signal among signaling by EGFR family of receptors. HER3 overexpression may lead to heterodimerization with HER2/neu receptors which may in turn lead to activation of downstream signaling pathways leading to tumor proliferation and growth.

Tumor selection of resistant clones

Treatment of HER2/neu positive serous endometrial tumors may induce the proliferation of HER2/neu negative clones within the tumor as a way of resistance. In a case report on two patients with initial tumor cells shown to be overexpressing HER2/neu by IHC and ErbB2 amplification by FISH, biopsy at the time of disease progression on trastuzumab therapy demonstrated loss of HER2/neu overexpression in the resistant tumors (65).

Overcoming resistance in HER2/neu targeted therapy

Resistance to HER2/neu targeted therapy can be mitigated in various ways. Combination of HER2/neu targeted therapy to a drug that acts on the downstream pathways is the most common strategy employed in such cases. Lopez et al. showed that combination therapy with neratinib and taselisib is found to produce stronger and long-lasting growth inhibition of tumor cell lines compared to either treatment alone. They also showed that combination therapy is effective even when initiated after tumor progression compared to single targeted therapy with either agent alone in mice xenografts that are HER2/neu and PIK3CA overexpressed/amplified (80). Combination of a intracellular HER2/neu targeting agent with a drug that targets extracellular domain is also a way of overcoming resistance (75).

Ongoing trials

Several ongoing trials are evaluating the efficacy of HER2/neu targeting agents in serous ECs. Most are basket trials which require tumors of different organs to harbour HER2/neu overexpression and/or amplification to be included in the trial.

DESTINY-Breast01 was a two-part open labelled phase 2 trial to evaluate the efficacy of trastuzumab deruxtecan on metastatic breast cancer patients who were previously treated with T-DM1. Trastuzumab deruxtecan showed a overall response rate (ORR) of 60.9% and a median PFS of 16.4 months (81). DESTINY-PanTumor02 trial is an open label phase II multicentre basket trial that evaluated the efficacy of trastuzumab deruxtecan in 40 patients with advanced or metastatic EC in addition to other tumors including biliary tract, bladder, cervical, ovarian, pancreatic, or other tumors (excluding breast, gastric, colorectal, and non-small cell lung cancer). Only patients with tumors expressing 2+/3+ were included in the study. The highest ORR among all tumor groups was observed in ECs at 57.5%. In uterine tumors that showed strong positivity (3+) for HER2/neu expression, the ORR was 84.6% (82,83).

MyPathway is a non-randomised phase 2a basket trial evaluating targeted therapy in solid tumors with specific molecular alterations which are not currently approved in clinical practice. The combination of pertuzumab and trastuzumab was used in HER2/neu overexpressing or amplified tumors including EC. Early reports published show no objective response in seven cases of HER2/neu positive EC recruited but conclusive results are still awaited (84). NCT04585958 is a phase II trial looking at the maximum tolerated dose of trastuzumab deruxtecan when combined with olaparib in HER2/neu expressing tumors including ECs (85). A multicentre phase II/III trial involving 172 centers in the USA is currently evaluating the effect of adding Trastuzumab or a combination of trastuzumab and pertuzumab in uterine carcinosarcomas and serous carcinomas (86).

Future directions

HER2/neu testing and interpretation varies between studies as demonstrated in this review and was mostly extrapolated from the ASCO/CAP guidelines for HER2/neu testing in breast cancer. Despite these extrapolated recommendations, testing criteria/guidelines specific to EC should be established as was done for breast (ASCO/CAP), gastric (ASCO/CAP) and most recently colorectal cancer (HERACLES trial) (50). The criteria employed by Fader et al. provides a basis upon which further trials can be designed towards standardising testing practices and interpretation (43).

It is observed that in addition to USC, other non-serous endometrial tumors also demonstrate HER2/neu overexpression and amplification. Whether these histological subtypes might derive benefit from HER2/neu targeted therapy is a question that needs to be answered. In this respect, molecular analysis of patients enrolled in PORTEC-3 trial showed that there was a stronger correlation between HER2/neu amplification and TP53 mutation than there is with serous cancer (16). The STATICE trial which evaluated the effect of trastuzumab on carcinosarcoma recently concluded that targeted therapy with trastuzumab deruxtecan, an ADC in which trastuzumab is linked to a topoisomerase I inhibitor, confers some benefit even in non-serous tumors (87). NCCN guidelines recommend HER2/neu IHC testing in patients with carcinosarcomas and TP53 mutations, in addition to advanced and recurrent serous ECs (60).

HER2/neu targeting agents appear to be clinically more meaningful in the primary treatment of advanced serous uterine cancers compared to recurrent settings. Novel antibody-drug conjugates and suitable combinations with immune check-point inhibitors and PI3K/Akt/mTOR inhibitors should be evaluated to improve outcomes in advanced and recurrent cancer. Another avenue that warrants investigation is the use of these agents in neoadjuvant setting for cases that are unsuitable for surgical cytoreduction. Early-stage serous ECs overexpress HER2/neu in approximately one quarter of the cases and HER2/neu positive serous cancers are associated with a significant increase in recurrence and death compared to HER2/neu negative serous tumors. Beyond prognostication, the role of HER2/neu as an actionable target in these tumor remains to be elucidated in early-stage serous ECs.

Conclusions

USC is a biologically aggressive disease associated with a poor prognosis. Alteration of HER2/neu pathway is a commonly found molecular aberration that contributes to aggressive behaviour of these tumors. Considering its negative prognostic implications and clinical benefit conferred by HER2/neu targeted therapy, HER2/neu testing is recommended for all cases of serous EC in advanced and recurrent settings. Trastuzumab in combination with platinum and taxanes based chemotherapy is the recommended treatment option for patients with advanced or recurrent serous cancers who test positive to HER2/neu. Role of HER2/neu as a therapeutic target in early-stage serous cancers remains to be seen but appears promising given that greatest benefits have been in patients treated with HER2/neu targeting agents in the first-line therapy. Focus of future research should be directed towards refining biomarker testing and selection of patients who will derive the most benefit from such therapy.

Acknowledgments

Funding: None.

Footnote

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