Therapeutics and toxicity management of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer: a narrative review

Introduction

Background

Approximately 20% of breast cancers overexpress or amplify the human epidermal growth factor receptor 2 (HER2). The development of anti-HER2 therapy has dramatically changed the prognosis of HER2-positive metastatic breast cancer (MBC), which is intrinsically aggressive (1,2). The introduction of trastuzumab deruxtecan (T-DXd) has reshaped treatment sequencing and management of adverse events (AEs).

Rationale and knowledge gap

Although current treatment has dramatically improved prognosis, several important questions remain regarding optimal sequencing, integration of novel agents, resistance mechanisms, and personalized supportive care.

Objective

We reviewed the currently available evidence for the systemic treatment of HER2 positive MBC, management of central nervous system (CNS) metastases, and supportive care for patients receiving anti-HER2 therapy. We aimed to describe the current challenges and future directions. We present this article in accordance with the Narrative Review reporting checklist (available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-25-29/rc).

Methods

A comprehensive literature search was conducted on 10 June 2025 using PubMed and Google Scholar. The search aimed to identify studies related to breast neoplasms, ErbB-2 (HER2), molecular targeted therapy, antibody-drug conjugates (ADCs), and tyrosine kinase inhibitors (TKIs). The timeframe for the search covered all publications up to 2025.

The inclusion criteria included research articles, reviews, or clinical guidelines that were written in English.

No restrictions were placed on study design beyond these inclusion criteria. The selection process was performed independently by two authors. Each author screened the titles and abstracts of retrieved articles. Full texts were reviewed when eligibility was unclear. Discrepancies between reviewers were resolved by consensus discussion. Additionally, a hand search of the reference lists of relevant studies and reviews was performed to identify any additional pertinent articles (Table 1).

Review

Trastuzumab and pertuzumab

For approximately 10 years, the standard first-line treatment for HER2-positive MBC was a combination of pertuzumab, trastuzumab, and docetaxel (THP). CLEOPATRA is a pivotal phase III study comparing the efficacy and safety of THP with placebo, trastuzumab, and docetaxel in patients with HER2-positive MBC (N=808) (3). Docetaxel was forgone after six cycles at the investigators’ discretion. The median progression-free survival (PFS) was 18.5 months in the pertuzumab group and 12.4 months in the placebo group [hazard ratio (HR), 0.62; 95% confidence interval (CI): 0.51–0.75; P<0.001], which met the primary endpoint. The secondary endpoint of overall survival (OS) was 56.5 months in the pertuzumab group compared to 40.8 months in the placebo group (HR, 0.68; 95% CI: 0.56–0.84; P<0.001), with a difference of 15.7 months. In the final analysis with a median follow-up nearly 100 months, the OS rates were 57.1 and 40.8 months in the pertuzumab and placebo group, respectively (HR 0.69; 95% CI: 0.58–0.82) (4). CNS metastasis remains a challenge, even with the CLEOPATRA regimen. The incidence of CNS metastasis as the first site of disease progression was similar between the groups at 13.7% in the pertuzumab group and 12.6% in the placebo group (5). The median time to development of CNS metastases as the first site of disease progression was 11.9 months in the placebo group and 15.0 months in the pertuzumab group (HR, 0.58; 95% CI: 0.39–0.85; P=0.0049). These data indicate the occurrence of CNS metastasis in the maintenance phase, which led to subsequent clinical studies such as the DESTINY-Breast09 and HER2-CLIMB05 studies. Worsening health-related quality of life until cycle 6 and recovery to baseline levels thereafter were observed in both groups (6). This decline was primarily attributable to docetaxel-induced AEs.

Phase III JBCRG-M06/EMERALD investigated the non-inferiority of eribulin, trastuzumab, and pertuzumab to taxane, trastuzumab, and pertuzumab as first-line treatments in patients with HER2-positive MBC as first-line treatment (7). The median PFS rates were 14.0 months in the eribulin group and 12.9 months in the taxane group, respectively (HR, 0.95; 95% CI: 0.76–1.19), which confirmed the noninferiority. AE rates were comparable between groups despite the longer duration of eribulin treatment. Patients in the taxane group more frequently experienced infusion reactions, skin-related AEs, diarrhea, and edema while patients in the eribulin group more frequently experienced neutropenia. The median time to deterioration of global health status in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Module C30 (EORTC QLQ C-30) was 7.16 months with eribulin group and 4.57 months with taxane group, which did not indicate a statistically significant difference (HR, 0.80; 95% CI: 0.66–0.99; P=0.08). Based on its non-inferior efficacy and different toxicity profiles, eribulin-based therapy has become a treatment option. When T-DXd and pertuzumab are the first-line treatments based on the ongoing DESTINY-Breast09 trial, the combination of eribulin, trastuzumab, and pertuzumab will become a second-line treatment option.

T-DXd

T-DXd is an ADC consisting of a humanized anti-HER2 monoclonal antibody linked to a derivative of exatecan, a potent topoisomerase I inhibitor, via a cleavable cathepsin linker (8). The drug-to-antibody ratio was 8. T-DXd exhibits strong antitumor effects even in tumor cells resistant to trastuzumab or T-DM1. In addition, its payload has high membrane permeability, leading to a potent bystander effect, which has been observed in HER2-negative cells adjacent to HER2-positive cells (9).

The DESTINY-Breast01 is a single-arm phase II study in patients with HER2-positive metastatic/recurrent breast cancer who had previously received T-DM1 (10). In part 1, three different dose levels were assessed to determine the recommended dose, whereas in part 2, the efficacy and safety of the dose were evaluated. The primary endpoint was the objective response rate (ORR), as assessed by an independent central review. A total of 184 patients with a median of six prior lines of therapy were treated with the recommended dose of 5.4 mg/kg T-DXd. The ORR was 60.9% (95% CI: 53.4–68.0%). The median duration of response was 14.8 months (95% CI: 13.8–16.9), and the median PFS was 16.4 months (95% CI: 12.7–not reached). The most common AE of grade 3 or higher was hematological toxicity. A total of 13.6% of the patients developed interstitial lung disease (ILD): grade 1 or 2 in 10.9%, grade 3 or 4 in 0.5%, and grade 5 (fatal) in 2.2%. Based on these results, T-DXd was approved for the treatment of HER2-positive metastatic/recurrent breast cancer in Japan in March 2020. The high ORR in heavily pretreated patients and the high ILD incidence have garnered attention. In November 2017, following the occurrence of fatal ILD cases suspected to be drug related, an external independent adjudication committee (AC) comprising pulmonologists and radiologists was established. This committee reviews all available computed tomography images and clinical data related to potential ILD/pneumonitis cases to assess the diagnosis and causality of T-DXd. AC assessments contribute to the early diagnosis and management of T-DXd-related ILD (11).

DESTINY-Breast03 is a phase III randomized controlled study comparing the efficacy of T-DXd and T-DM1 in patients with HER2-positive MBC (12). The primary endpoint was PFS, which was assessed by a blinded independent central review. Among the 524 patients enrolled, the 12-month PFS rate was 75.8% in the T-DXd group (95% CI: 69.8–80.7%) vs. 34.1% in the T-DM1 group (95% CI: 27.7–40.5%) (HR, 0.28; P<0.001). At the time of the first interim analysis, the median PFS was not reached in the T-DXd group (95% CI: 18.5–not estimable) and was 6.8 months in the T-DM1 group (95% CI: 5.6–8.2). The 12-month OS rate was 94.1% in the T-DXd group (95% CI: 90.3–96.4) vs. 85.9% in the T-DM1 group (95% CI: 80.9–89.7); however, the median OS was not reached in either group (HR, 0.55; P=0.007), and the prespecified boundary for statistical significance was not met owing to the low number of events. In a subsequent update, the second interim analysis showed a statistically significant OS advantage for T-DXd over T-DM1 (HR, 0.64; P=0.0037), and the PFS remained superior in the T-DXd group (13). The ORR [complete response (CR) or partial response (PR)] was 79.7% (95% CI: 74.3–84.4%) in the T-DXd group and 34.2% (95% CI: 28.5–40.3%) in the T-DM1 group, with CR observed in 16.1% and 8.7%, respectively. With longer follow up at the data cut-off on November 2023, the median OS reached 52.6 months [95% CI: 48.7–not estimate (NE)] with T-DXd and 42.7 months (95% CI: 35.4–NE) with T-DM1; the risk of death was reduced by 27% with T-DXd compared to T-DM1 (HR, 0.73; 95% CI: 0.56–0.94) (14). The DESTINY-Breast03 phase III trial changed the standard of care for the second-line treatment of HER2-positive metastatic/recurrent breast cancer.

Recently, an interim analysis from the DESTINIY-Breast09 trial demonstrated the superiority of the doublet of T-DXd + pertuzumab (T-DXd + P) over THP in terms of PFS as a first line treatment in patients with HER2-positive MBC (15). T-DXd + P significantly improved PFS evaluated by blinded independent central review (HR, 0.56; 95% CI: 0.44, 0.71; P<0.00001). OS data were immature. Grade ≥3 treatment-emergent AEs (TEAEs) occurred in 63.5% of patients in the T-DXd + P group and 62.3% in the THP group with serious TEAEs in 27.0% and 25.1%. Adjudicated drug-related ILD/pneumonitis occurred in 46 patients in T-DXd + P group [12.1%; predominantly grade 1/2; n=2 (0.5%) grade 5] and 4 patients in THP group (1.0%; all grade 1/2), respectively. If T-DXd becomes a first-line option, management of acute and long-term toxicity is critical.

Tucatinib

Tucatinib is a reversible oral tyrosine kinase inhibitor with high selectivity for the HER2 kinase domain and minimal affinity for EGFR (16). HER2CLIMB is a randomized phase 2 study that included patients with HER2-positive MBC who had received prior treatment with trastuzumab, pertuzumab, and T-DM1. The study included patients with brain metastases unless they needed immediate local therapy. The patients were randomized in a 2:1 ratio to receive either tucatinib or placebo in combination with capecitabine and trastuzumab. The 1-year PFS rate was 33.1% in the tucatinib group and 12.3% in the placebo group (HR, 0.54; 95% CI: 0.42–0.71, P<0.001), and the median PFS was 7.8 vs. 5.6 months. The 2-year OS rate was 44.9% in the tucatinib group and 26.6% in the placebo group (HR, 0.66; 95% CI: 0.50–0.88; P=0.005), and the median OS was 21.9 and 17.4 months, respectively. Among the patients with brain metastases, the 1-year PFS rate was 24.9% in the tucatinib group compared to 0% in the placebo group (HR, 0.48; 95% CI: 0.34–0.69; P<0.001), and the median PFS was 7.6 vs. 5.4 months. The tucatinib combination regimen was well tolerated among patients with or without brain metastasis. The common AEs in the tucatinib group were diarrhea (80.9%), palmar-plantar erythrodysesthesia syndrome (63.4%), nausea (58.4%), fatigue (45.0%), and vomiting (35.9%).

Currently, the tucatinib-trastuzumab-capecitabine combination is used as the third- or later line treatment in general, and as the second-line treatment option for patients with active brain metastasis (17,18). In a retrospective cohort study (n=101) that included patients with HER2-positive MBC who received the tucatinib-trastuzumab-capecitabine combination after T-DXd exposure, the median PFS was 4.7 months (95% CI: 3.9–5.6), and the median OS was 13.4 months (95% CI: 11.1–not reached) (19). Sixteen patients with active brain metastasis had a median PFS of 4.7 months (95% CI: 3.0–7.3), and the median OS of 12.4 months (95% CI: 8.3–not reached). The tucatinib-trastuzumab-capecitabine combination is a good treatment option for T-DXd-resistant cases.

Brain metastasis

Approximately 30–50% of patients with HER2-positive MBC ultimately develop brain metastases, which is associated with a poorer prognosis compared to patients without brain metastases (20,21).

The DESTINY-Breast12 was a phase IIIb/IV study that evaluated the efficacy of T-DXd in patients with HER2-positive MBC, including those with brain metastases (22). The study enrolled 263 patients with stable or active brain metastases and 241 patients without brain metastases. All the patients received T-DXd at a dose of 5.4 mg/kg. In the brain metastasis cohort, the 12-month PFS rate was 61.6%, and the 12-month CNS-PFS rate was 58.9%. In the non-brain metastasis cohort, the ORR was 62.7%. This large trial demonstrated that T-DXd has comparable efficacy in patients with and without brain metastases, including those with intracranial activity. These findings are important not only for breast cancer but also for other HER2-expressing cancers prone to brain metastases.

Roset-BM is a retrospective study that evaluated the effectiveness and safety of T-DXd in patients with HER2-positive breast cancer with active or stable brain metastasis in a real-world setting (23). This study included 104 patients with brain metastases and leptomeningeal disease (N=104). The ORR based on the investigator’s assessment was 55.7%. The median PFS was 16.1 months, and the 12-month OS rate was 74.9%. The IC-ORR and median IC-PFS by independent central review were 62.7% and 16.1 months in patients with BM imaging. In 19 patients with leptomeningeal disease, the 12-month PFS and OS rates were 60.7% and 87.1%, respectively. Given the poor survival of patients with breast cancer and leptomeningeal disease (1-year OS rate 16–24%) with limited treatment options, T-DXd has emerged as a valuable option for this population (24,25).

HER2-CLIMB demonstrated the efficacy of tucatinib combination therapy in patients with HER2-positive breast cancer and active or stable brain metastases (26,27). At baseline, 291 of the 612 patients (47.5%) had brain metastases. In the subgroup of brain metastasis, the median CNS-PFS was 9.9 months in the tucatinib group and 4.2 months in the placebo group, respectively. In active brain metastasis (untreated or treated and progressing brain metastases) cohort, the median CNS-PFS was 9.5 months in tucatinib group and 4.1 months in the placebo groups, respectively. A confirmed ORR-IC of 47.3% was observed in the tucatinib group and 20.0% in the placebo group. Among the entire intention-to-treat study population, the median new brain lesion-free survival was 24.9 months in the tucatinib group compared with 13.8 months in the placebo group.

These data support the tucatinib combination for patients with asymptomatic and stable brain metastases, which could reduce the need for upfront local therapy including stereotactic radiosurgery. Local therapy is recommended for symptomatic and active metastases in accordance with the clinical guidelines (28). Stereotactic radiosurgery is generally safe, although it is associated with late complications of cerebral radiation necrosis (29). Therefore, initiating systemic therapy to postpone local therapy could be a reasonable approach for selected patients even with active metastases. As patients with HER2-positive breast cancer achieve long-term survival, treatment sequencing, management of long-term side effects, and maintenance of the quality of life should be carefully considered.

Trastuzumab emtansine (T-DM1)

T-DM1 is an ADC in which trastuzumab is conjugated via a non-cleavable linker to DM1, a maytansine derivative that inhibits microtubules. The DAR is 3.5. In metastatic/recurrent HER2-positive breast cancer, based on the results of the EMILIA trial, T-DM1 has long been used as a second-line treatment following disease progression after first-line therapy with trastuzumab, pertuzumab, and taxane (30). However, following the results of the DESTINY-Breast03 trial, T-DM1 is now primarily used as a third-line treatment or after T-DXd (12). Although the evidence on T-DM1 after progression on T-DXd is scarce, its limited efficacy is expected because loss or decreased expression of HER2 is common after T-DXd treatment (31,32). T-DM1 would be an option for those with T-DXd contraindicated or other resistance mechanisms such as against the payload, deruxtecan.

Novel drugs to overcome T-DXd resistance

An effective systemic therapy for T-DXd-resistant HER2-positive MBC is needed. Zanidatamab is a bispecific HER2-directed antibody that binds to two distinct extracellular sites (ECD2 and ECD4) in HER2. The binding of zanidatamab to HER2 results in its internalization, leading to a reduction of HER2 expression on the tumor cell surface. Zanidatamab induces complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, and antibody-dependent cellular phagocytosis (33). A phase III study comparing the efficacy and safety of zanidatamab in combination with physician’s choice of chemotherapy to those of trastuzumab in combination with physician’s choice of chemotherapy, for the treatment of patients with HER2-positive MBC (NCT06435429) is ongoing. This study recruits patients who had progressed or were intolerant of previous T-DXd treatment.

Cardiac toxicity management

Cancer therapy-related cardiac dysfunction is a common problem during anti-HER2 therapy. Neuregulin (NRG-1) is a ligand for the ErbB family, and the NRG-1/ErbB signaling pathway promotes cardioprotection (34). Trastuzumab-induced cardiac dysfunction may result from inhibition of the NRG-1/ErbB pathway in cardiomyocytes (34). The highest risk of trastuzumab-induced cardiotoxicity is observed in patients aged >50 years , those with pre-existing cardiovascular disease or hypertension, those with a baseline left ventricular ejection fraction (LVEF) of ≤50–55%, and those with a history of anthracycline therapy (35). The treatment of pre-existing cardiac vascular risk factors according to current guidelines is recommended (36). Although trastuzumab-related cardiac dysfunction is generally reversible, patients previously treated with anthracyclines may develop severe cardiac dysfunction because of combined cardiotoxic effects. Therefore, these patients should be monitored carefully (35). In the long-term follow-up of the CLEOPATRA study, the incidence of left ventricular dysfunction was 8% in the pertuzumab group (grade ≥3; 1%) and 9% in the placebo group (grade ≥3; 3%) (4), indicating no significant increase of cardiac toxicity upon addition of pertuzumab. In the DESTINY-Breast 03 trial, a decrease in the ejection fraction was observed in six patients (2.3%) in the T-DXd group and in one patient (0.4%) in the T-DM1 group, all of whom had grade 2 left ventricular dysfunction (12). Additionally, one patient in the T-DXd group developed grade 1 left ventricular dysfunction (12). All patients were asymptomatic. In patients receiving trastuzumab or anti-HER2 ADC treatment, the LVEF should be monitored by transthoracic echocardiography before treatment and at regular intervals (approximately 3 months) during treatment if asymptomatic (37). When transthoracic echocardiography cannot be performed, such as in cases of extensive cancerous skin ulcers, magnetic resonance imaging or multi-gated acquisition (MUGA) scan may be considered as alternatives. However, MUGA can only assess LVEF and does not provide other evaluations. In the case of a decrease in LVEF, anti-HER2 therapy should be paused or discontinued per the direction on the labels, depending on the severity of the LVEF decrease. Oral anti-HER2 tyrosine kinase inhibitors generally have a low risk of cardiovascular toxicity. No major cardiovascular AEs were observed after tucatinib treatment in the HER2CLIMB trial (19).

Management of nausea and vomiting

T-DXd plays a central role in the long-term treatment journey of HER2-positive MBC. Managing its side effects, especially nausea, is essential, as it greatly affects the patients’ quality of life. Approximately 70% of patients receiving T-DXd treatment experienced any-grade nausea, and approximately 40% experienced any-grade vomiting in DESTINY trials (12,38). Although most cases are mild (grade 1 or 2), some patients experience severe nausea and vomiting.

There is inconsistency across clinical guidelines regarding the emetic risk of T-DXd and recommended antiemetic therapy options (Table 2). In addition to various emetic risks and recommended antiemetic regimens, individual variations in symptoms and difficulty in assessing patient-specific risk factors complicate treatment decisions. Drug availability and costs vary across countries and regions. Some physicians prefer a more aggressive prophylactic approach, whereas others adopt a stepwise approach.

Two prospective phase II studies have evaluated the efficacy of antiemetic therapy in patients with breast cancer receiving the first cycle of T-DXd treatment. A study by Iihara et al. randomized patients with HER2-positive MBC (n=40) to receive either a doublet regimen (granisetron and dexamethasone and) or triplet regimen (aprepitant or fosaprepitant in addition to the doublet regimen) as a prophylactic antiemetic therapy for T-DXd (42). The CR rates in the overall phase (0–120 h) were 36.8% in the doublet regimen group and 70.0% in the triplet regimen group (P=0.0190), representing a difference of 33.2%. The CR rate in the extended overall phase (0–168 h) was higher in the triplet regimen group than doublet regimen group (70.0% vs. 31.6%, P=0.0087), with a difference of 38.4%. The ERICA study by Sakai et al. randomized patients with HER2-positive or HER2-low MBC (n=168) to receive either olanzapine (5 mg) or placebo once daily for 6 days, in addition to 5-HT3RA and dexamethasone (6.6 mg intravenously or 8 mg orally on day) as a prophylactic antiemetic therapy for T-DXd (43). The CR rate in the delayed phase (24–120 h) was 70.0% in the olanzapine group and 56.1% in the placebo group, representing a difference of 13.9% (P=0.047). The CR rate in the persistent phase (120–504 h) was higher in the olanzapine group than in the placebo group (64.9% vs. 44.4%; difference, 19.4%). The daily CR and daily no-nausea rates were consistently higher in the olanzapine group throughout the 21-day observational period. In these two studies, the CR rate was low in the doublet regimen arms, suggesting that prophylactic antiemetic therapy with three or more agents is necessary for T-DXd treatment. Although determining whether olanzapine or an NK1 receptor antagonist should be preferred was not possible, several considerations are important, such as that olanzapine is particularly effective in controlling delayed-phase nausea, that some patients cannot tolerate it because of side effects, such as drowsiness or diabetes, and that it is less expensive than NK1 receptor antagonists. Therefore, the choice of these agents should be individualized based on patient-specific factors. In patients with high-risk factors, such as a history of severe nausea and vomiting, young age, and female sex, a four-drug regimen can be administered.

ILD management

The emergence of T-DXd has attracted increasing attention for ILD management. In the DESTINY-Breast03 trial, 10.5% of the patients developed pneumonitis/ILD according to an independent adjudication panel, with a median time to onset of 5.5 months (range, 1–16.7 months). All cases were grades 1-3 (median follow-up of 16.2 months), with the majority of cases resolved (70.3%) (12).

A post marketing surveillance on T-DXd-induced ILD in 1,731 patients with MBC was conducted in Japan, and the incidence of adjudicated drug-related ILD/pneumonitis were 16.1% (any grade), 3.0% (grade ≥3), and 1.0% (grade 5), respectively. A multivariate analysis identified several factors associated with the development of ILD/pneumonitis: medical history and/or comorbidity of ILD/pneumonitis (HR, 2.237; 95% CI: 1.210–4.134), baseline renal impairment [mild impairment (HR, 1.719; 95% CI: 1.272–2.322)], moderate impairment to end stage (HR, 1.850; 95% CI: 1.240–2.761), higher body mass index (HR, 1.649; 95% CI: 1.275–2.133), and male sex (HR, 3.634; 95% CI: 1.299–10.163) (44).

Proactive monitoring thorough interviews, pulse oximetry, and computed tomography scans is necessary for early diagnosis of ILD. Collaboration among medical oncologists, nurses, radiologists, and pulmonologists enables timely care. In the case of T-DXd-induced ILD, treatment with corticosteroids may be considered even in patients with grade 1 ILD (radiological findings without symptoms). Finally, patient education is a key component of ILD management. Patients should be encouraged to report even mild symptoms, including cough, dyspnea, fever, and fatigue (11).

Conclusions

The development of anti-HER2 therapies has dramatically transformed the treatment landscape for HER2-positive MBC. For nearly a decade, the standard first-line therapy has been a combination of THP. However, T-DXd is now being reshaped as the gold standard. T-DXd could also alter the management of CNS metastases. Nevertheless, effective treatment of T-DXd progression is still needed, and several novel agents are currently developed. In addition, managing side effects remains a key challenge, particularly in patients who experience a durable response to T-DXd. Tucatinib is a treatment option for patients with brain metastasis or T-DXd-resistant disease. The role of T-DM1 is limited in both current and future treatment landscapes.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-25-29/rc

Peer Review File: Available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-25-29/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-25-29/coif). H.S. has received speaker’s fees from Daiichi Sankyo, Eli Lilly, AstraZeneca, and Gilead Sciences; and medical writing support from Daiichi Sankyo, all outside the submitted work. J.T. has received speaker’s fees from AstraZeneca, Daiichi Sankyo, Pfizer, Chugai, Eisai, and Nihon Kayaku; payment for expert testimony from Pfizer and Daiichi Sankyo; advisory board fees from AstraZeneca, Daiichi Sankyo, Pfizer, and Gilead; and medical writing support from Daiichi Sankyo, all outside the submitted work. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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