Escalation and optimisation of primary breast cancer treatment with antibody-drug conjugates

Introduction

The clinical application of antibody-drug conjugates (ADCs) started with human epidermal growth factor receptor 2 (HER2)-positive recurrent metastatic breast cancers. Trastuzumab-DM1 (T-DM1), which uses the microtubule inhibitor DM1 as its payload, was developed and was first approved by the Food and Drug Administration for patients with multiple-line failures of HER2-positive recurrent breast cancer and then quickly approved worldwide (1-5). Its usefulness as a second-line treatment has been established. Trastuzumab-deruxtecan (T-DXd) was introduced following T-DM1 (6-9). T-DXd targets HER2 like T-DM1 and uses trastuzumab as the antibody but conjugates the topoisomerase-1 (TOPO-1) inhibitor deruxtecan as the payload. Cellular and animal experiments have shown that T-DM1 has a low bystander effect among tumour cells, whereas T-DXd exerts a potent bystander effect (8,9). For example, in tumours with a mixture of strongly and weakly HER2-positive tumour cells, T-DXd exhibits a more potent anti-tumor effect than T-DM1. T-DM1 showed a remarkable anti-tumour effect in HER2 homogenously over-expressing tumours, but its efficacy seemed limited in tumours with heterogenous HER2 expressions (10). T-DXd is significantly superior to T-DM1 in progression-free survival (PFS) and overall survival (OS) and has become the standard treatment for second-line treatment (11,12). Its usefulness in the first line is currently being evaluated, and various studies on optimal sequences and positioning are underway (13). ADC-ADC sequence has also been investigated (14-16). T-DXd has demonstrated clinical effectiveness not only in HER2-positive cases but also in HER2-low expressing and hormone receptor (HR)-positive cases, which was expected in laboratory experiments (8,17,18). Compared with physician’s choice (conventional chemotherapy), T-DXd showed superior PFS and OS in these diseases (19,20). Therefore, it has been incorporated into the standard treatment for all recurrent metastatic breast cancers except tumours without HER2 expression (21-25).

Sacituzumab govitecan (SG) targets a tumour-associated calcium signal transducer (TROP)-2 and conjugates a TOPO-1 inhibitor as a payload (26,27). Since TROP2 expression is identified in most triple-negative breast cancers (TNBC), clinical development was conducted with TNBC as the primary target (28,29). In treating recurrent advanced TNBC, SG showed superior results in PFS and OS compared to conventional chemotherapy treatments. The SG, like T-DM1 and T-DXd, has become available in many countries worldwide (30-34). What these three ADCs have in common is their favourable treatment outcomes for brain metastases (BM) and their impact on prognosis (35-39). Although the mechanism is not entirely clear, and there are differences in the efficacy between the drugs, all three drugs are highly effective against BM, which has not been seen before.

In addition, clinical trials of many ADC drugs, such as datopotamab-deruxtecan (DATO-DXd), trastuzumab-dacarbazine and paritumab-deruxtecan (PAT-DXd), are being conducted for recurrent and advanced breast cancer (40-43). Phase 3 trials of DATO-DXd as neoadjuvant and adjuvant therapy have also been initiated (44,45). Many ADCs are designed to combine multiple therapeutic targets and multiple payloads (46-50).

Combination therapies are also being actively investigated. For example, immuno-oncology (IO) drugs such as programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) antibodies, and endocrine therapy (ET) (51-57). Overall, many drugs and combination therapies are being clinically tested not only for recurrent and advanced breast cancer but also for primary breast cancer.

Neoadjuvant ADC for HER2-positive primary breast cancer

T-DM1 has also been shown to be effective as a neoadjuvant therapy for primary breast cancer (58-60). Multiple clinical trials have been conducted on T-DM1, partly because the incidence of severe toxicity is relatively low (61-64). Direct comparisons with standard therapies such as docetaxel + carboplatin + trastuzumab + pertuzumab (TCbHP) were carried out, but they showed inferior results in pathological complete response (pCR) rate for the T-DM1 group (59). Still, invasive disease-free survival (iDFS) comparisons showed almost equivalent results, although event-free survival (EFS) was inferior. As described above, heterogeneity in HER2 expression can hinder the achievement of a high response rate from T-DM1 alone (10). In the Japan Breast Cancer Research Group (JBCRG)-20 study, a randomised phase II trial was conducted in the TDM-1 + pertuzumab arm, which does not use conventional cytotoxic anticancer drugs, the TCbHP arm and the TCbHP followed by TDM-1 + P arm (60). If it was determined that sufficient efficacy was not obtained in the TDM-1 + P arm, an anthracycline-containing chemotherapy was added. The highest pCR rate for ypT0/is ypN0 was achieved in the TCbHP followed by TDM-1 + P arm (TDM-1 + P arm 57%, TCbHP arm 57%, TCbHP followed by TDM-1 + P arm 71%, respectively). It was remarkable that a high pCR rate (69%) was achieved in the ER-positive subgroup of the TCbHP followed by TDM-1 + P arm. Regarding prognosis, the 5-year DFSs of the three arm groups were 88%, 92.3%, and 91.8%, respectively, with no significant difference between these groups (65). The ADAPT trial evaluated the efficacy of neoadjuvant therapy with T-DM1 alone or T-DM1 + ET in HER2⁺ and HR⁺ cases. The pCR rates for the T-DM1 alone group and the T-DM1 + ET group were reported to be 41% and 41.5%, respectively. The pCR rate in the trastuzumab + ET group was 15.1%, demonstrating the magnitude of the antitumor effect of ADCs containing DM1 in the HR⁺/HER2⁺ subgroup (61). On the other hand, the combination of ET did not show any significant impact, at least in improving the pCR rate. Taken together, neoadjuvant T-DM1 has not been used globally at the routine practical level.

T-DXd is expected to exert a higher efficacy than T-DM1 against HER2-positive breast cancer because it has bystander activity that overcomes HER2 heterogeneity. In addition to several phase 2 trials, a phase 3 trial, the Destiny Breast11 study, is currently being conducted (66-70). The trial design compares T-DXd alone with T-DXd followed by paclitaxel + HP (trastuzumab + pertuzumab) and dose-dense anthracycline + cyclophosphamide (ddAC) followed by paclitaxel + HP (66). The efficacy of T-DXd in the neoadjuvant setting and the significance of combining T-DXd with taxanes in series can be verified by comparing it with the currently representative regimen, ddAC, followed by paclitaxel + HP. A direct comparison with TCbHP is also conducted in the phase 2 trial (67-69).

Adjuvant ADC for HER2-positive primary breast cancer

Two significant directions have been considered in postoperative adjuvant therapy. One is its application to patients with a high risk of recurrence, such as those with residual invasive disease after neoadjuvant treatment, and the other is T-DM1 monotherapy for early-stage breast cancer with small tumour size and no lymph node metastasis, such as stage 1 (3,70,71).

Regarding therapy escalation, excellent results were shown in the Katherine trial (3). The subject enrichment strategy is the same concept as that used in the Create X trial of capecitabine (72). For therapy-resistant high-risk micrometastases, treatment escalation has been performed using a therapy that is thought to have less cross-resistance. Compared with trastuzumab +/− ET, T-DM1 +/− ET showed a favourable recurrence suppression effect with a hazard ratio of 0.5 (3). This method has now become the global standard. Based on the results of the Katherine trial, two new strategies are being tested in clinical trials. One strategy combines T-DM1 with atezolizumab or the tyrosine kinase inhibitor tucatinib, and the other is T-DXd, replacing T-DM1 (73,74). Phase 3 clinical trials are currently underway for both methods.

Recently, the results of a new anti-HER2 ADC SHR-A1811, which was created using a MC-Gly-Gly-Phe-Gly (GGFG)-linker with the new TOPO-1 inhibitor SHR169265 as a payload, in the neoadjuvant setting for HER2-positive primary breast cancer have been reported (75,76). This was a phase II comparative study of three groups: SHR-A1811 alone for eight cycles, SHR-A1811 plus pyrotinib, and PCbHP (nab-paclitaxel, carboplatin, trastuzumab, pertuzumab) for six cycles. The pCR rates were 63.2% in the SHR-A1811 alone group, 62.5% in the SHR-A1811 plus pyrotinib group, and 64.4% in the PCbHP group. All three groups achieved similar pCR rates, and no significant differences were observed between the three groups. Interestingly, the SHR-A1811 alone group achieved a pCR rate comparable to that of the PCbHP group. A phase 3 trial directly comparing SHR-A1811 with T-DM1 in the postoperative adjuvant setting for HER2-positive residual invasive disease is also currently underway (77).

The latter is a de-escalation strategy that replaces paclitaxel + H(P), the standard treatment for stage 1 HER2-positive cancer, with T-DM1 (71,78). Although no direct comparison has been conducted due to the highly favourable prognosis of the subjects, the 5-year iDFS rate of the T-DM1 alone group was reported to be around 97%. Although it is not necessarily reimbursed by insurance worldwide, it is an important treatment option for eligible patients.

Tables 1,2 summarise the major outcomes from neoadjuvant and adjuvant trials with ADC for HER2-positive breast cancers (79,80).

ADC for TNBC

In the phase 2 neoadjuvant trial, anti-TROP2 ADC SG achieved a pCR rate of 30% and an overall response rate of 64% with four cycles of SG monotherapy (81). Four treatment cycles appear to be comparable to anthracycline and taxane combination therapy. Standard neoadjuvant systemic therapy for stage 2/3 TNBC is pembrolizumab + TCb (paclitaxel and carboplatin), followed by an anthracycline-containing regimen. For residual invasive disease, standard postoperative pembrolizumab + capecitabine or olaparib for BRCA1/2 pathogenic germline variants (PGVs). The AFT-65/ASCENT 05/OptimICE-RD phase 3 trial tests the utility of eight cycles of pembrolizumab + SG against these conventional treatment regimens (53,82,83). The SASCIA phase 3 study, also considered critical research, compares eight cycles of SG with the physician’s choice for residual invasive TNBC and luminal cancers after preoperative systemic therapy (83). If successful, this will further improve the prognosis of TNBC patients. Meanwhile, a study using another anti-TROP2 ADC, DATO-DXd, examines its application as neoadjuvant therapy for patients with TNBC and HER2-/HR low or HER2⁻/HR⁺. The I-SPY2.2 study examined the utility of DATO-DXd + anti-PD-L1 durvalumab followed by standard chemotherapy regimens under response-guided de-escalation and escalation therapy concepts (54). If an early response is observed, subsequent chemotherapy is de-escalated, and standard chemotherapy is escalated if the response is poor. Although the number of cases examined is relatively small, reasonable PCR results were obtained (estimated pCR rate 41%), which is considered one of the guidelines for future treatment development. In addition, this study used a genomic assay to assess DNA repair deficiency activity and immunotherapy responsiveness. It demonstrated a high pCR rate of the DATO-DXd + durvalumab starting regimen in these high-risk tumours. As well known, these biological features are more frequently observed in TNBC than in luminal carcinoma. TROPION-Breast04 can be regarded as a partial extension of this study (44). This phase 3 study was designed to compare eight cycles of DATO-DXd + durvalumab head-to-head pembrolizumab + TCb followed by anthracycline in patients with TNBC. ADC for TNBC diseases is presented in Table 3.

ADC for HER2-negative breast cancer

The iSPY2.2 above has been reported as an ADC therapy for HER2-negative breast cancer. The pathological response rate in HR⁺ subgroup was somehow limited (54). Exploratorily, T-DXd neoadjuvant therapy has been performed as a phase 2 study, TRIO-US B-12 TALENT trial (84). Although the pCR rates of eight cycles of T-DXd +/− ET anastrozole therapy were limited (0.6% and 0%, respectively), objective response rates (ORRs) of these two arms treatments were 75% and 63%, respectively, suggesting that only a limited number of cases can achieve pCR with ADC monotherapy in HR⁺/HER2⁻ breast cancer. We may need a new therapeutic concept for the ADC application to HER2-negative luminal diseases.

Multiple phase 2 trials of the anti-HER3 ADC patritumab-deruxtecan (PAT-DXd) have also been conducted. Recently, results of the SOLTI TOT-HER3 part A and part B have been reported (42,85). In this trial, the impact of a single-dose treatment of PAT-DXd was investigated, and 45% of ORR was discovered. The therapy significantly induced immune-cell infiltration and tumour subtype change in responders. In addition, low HER2 mRNA was associated with the activity of PAT-DXd (86). A phase 2 study, SOLTI VALENTINE trial, showed that the PAT-DXd achieved a pCR rate of 4.0% and an ORR of 70.0% (N=50), respectively. Combined with letrozole (N=48), the pCR rate was 2.1% and the ORR was 81.3%, and in standard chemotherapy with anthracycline and cyclophosphamide (N=24), the pCR rate was 4.2% and the ORR was 70.8%, respectively. Grade 3 or higher toxicities were observed in 14.0%, 14.6%, and 45.8% in the PAT-DXd alone, PAT-DXd + letrozole and standard chemotherapy group, respectively (86). These results indicate that ADC like PAT-DXd may drive a high ORR with less toxicity than conventional chemotherapy, though pCR rates may not be high. In Table 3, significant outcomes are summarised.

Toxicity

Clinical trials of ADCs as neoadjuvant adjuvant therapy for primary breast cancer use regimens with 3–8 cycles. During this administration period, the incidence of various toxicities tends to increase, although this varies depending on the drug. Interstitial lung diseases (ILD) and toxicities that require treatment delay, interruption, or discontinuation, such as gastroenterological toxicity and fatigue, are crucial (28,87-89). Even though most of these data have been accumulated in clinical trials for recurrent breast cancer, these adverse events not only deteriorate the QOL significantly but also may cause loss of the opportunity to have appropriate standardised treatments in primary breast cancer patients. Therefore, toxicity management is essential for adequately using these ADCs in primary breast cancer setting. Regional differences in the incidence of ILD have also been noted (89). Each institution should have sufficient experience, knowledge, and skills in ADC toxicity management, and it is warranted to collect and analyse the data comprehensively.

Discussion

In the development of ADCs for primary breast cancer, many clinical trials are designed to maximise the properties of the drug. Preoperative therapy, especially for HR-negative stage 2/3 breast cancer, requires harsh and highly toxic treatment (90-92). The strategy of using ADCs, having different toxicity profiles from conventional chemotherapy drugs and using TOPO-1 inhibitors, which have not been used much in breast cancer treatment until now (90-92), seems attractive as a tool to create a new therapeutic paradigm that pursues high therapeutic effect, less toxicity and improves the balance between merits and demerits.

As a trend, neoadjuvant and adjuvant therapy using ADC is being developed in de-escalation and escalation directions (Figure 1). For breast cancer with a low risk of recurrence, new standard treatments engaged with ADCs are being explored after careful staging and molecular profiling (93-95). On the other hand, for patients with a high risk of recurrence and poor prognosis, such as residual invasive diseases remaining after preoperative systemic therapy (90-92), the development of standard treatment + ADC therapy is progressing. In the intermediate-risk group, the replacement of standard treatment with ADCs is being investigated. A response-guided approach is used in the treatment escalation and replacement process. Treatment-induced toxicity must be minimised in the treatment of low-risk patients. Regarding economic toxicity, replacing existing treatments with less toxic and less expensive therapies is desirable, especially in low-risk cases, but this might not be easy to realise, considering the current cost of ADCs (96-98).

Figure 1 Neoadjuvant and adjuvant therapy concept with antibody-drug conjugates for primary breast cancer patients. Neoadjuvant and adjuvant therapy using ADCs is being developed in de-escalation and escalation directions. For breast cancer with a low risk of recurrence, new standard treatments engaged with ADCs are being explored after careful staging and molecular profiling using genomic assays. On the other hand, for advanced breast cancer with a high risk of recurrence and poor prognosis, such as residual invasive diseases remaining after preoperative drug therapy, the development of standard treatment + ADC therapy is progressing. In the intermediate-risk group, the replacement of standard treatment with ADCs is being explored. A response-guided approach is used in the treatment escalation process. Treatment-induced toxicity must be minimised in low-risk treatments. Regarding economic toxicity, replacing existing treatments with less toxic and less expensive therapies in low-risk cases is desirable, but this is not easy considering the cost of ADCs. ADCs, antibody-drug conjugates.

Concerning clinical trial performance, studies designed to target residual invasive disease are suitable for achieving the result in a relatively short period because the baseline expected prognosis of the standard treatment (control) group is poor (3,72). On the other hand, trials in the intermediate-risk groups tend to require more time to prove their usefulness. The time it takes to get results is key because the same drug is often used in these trials, targeting high-risk and intermediate-high-risk patients. In general, we first obtain the results from the study for high-risk patients. While both results are positive, we must know that these two approaches may pose subtle complications when applied to clinical practice.

The combination of ADC with IO is being investigated intensively in neoadjuvant settings. Multi-drug combination therapy of taxane, platinum, anthracycline, cyclophosphamide, and anti-PD-1 has been standardised for TNBC. A combination of the ADC containing TOPO-1 inhibitor and IO seems intriguing and should be tested in this setting (90-92). Clinical results for these combination therapies are beginning to appear, and the development of efficacy predictors and prognostic factors for ADC + IO therapy is underway (54,99). Recent studies have revealed some aspects of the immunological response induced by treatment, which is detected at an early stage after treatment—initial results regarding what kind of profile will emerge and change in the tumour microenvironment when IO is given (100). Further studies must be verified and executed when ADC and IO are engaged, which will undoubtedly contribute to developing IO and ADC research in breast cancer. Although the combination of IO is not yet standard in neoadjuvant/adjuvant therapy for luminal diseases, the additive effect of pCR in neoadjuvant situations has been reported (101), and an impact on prognosis is expected. It is well known that the biological properties and drug sensitivity of HR-positive tumours differ from that of TNBC (102). Therefore, a different strategy from that for TNBC treatment may be necessary. However, based on the data so far, the effect of combining with hormone therapy is not necessarily apparent (84). The usefulness of dose-dense therapy has been established in conventional chemotherapy (103). Given the toxicity profile, increasing the dosing of ADC will not be easy. Therefore, a different strategy needs to be considered. A deeper study of the treatment sequence will probably be helpful.

We should also closely engage in translational research, especially on predictive biomarkers, and analyse patient-reported outcomes. Many unknowns remain regarding the sensitivity and resistance mechanism of ADCs. The molecular characteristics of the tumour and host condition and host reactions to the treatment will be critical for analysing them (56). This will improve the treatment of primary breast cancer patients.

Many new ADCs, using different target epitopes and payloads, are being developed. Some may also be designed for neoadjuvant and adjuvant therapy. These considerations will be helpful in the clinical development of drugs (46-50,104,105).

Limitations for reviewing ADC for primary breast cancers are: (I) although many studies have been initiated recently, most of their outcomes are still unreported. Only limited data are currently available. (II) Therapy escalation with ADC for patients who expected poor prognostic outcomes, especially those with residual invasive diseases after preoperative standard systemic therapy, will be successful because the residual tumour cells are resistant to conventional chemotherapies but have not been exposed to topoisomerase inhibitors, which meets the non-cross resistant chemotherapy sequence strategy. Nevertheless, many remain unclear about the superiority or equivalence of ADC to conventional chemotherapy combinations consisting of taxane, platinum and anthracycline and their intensified regimens. Its value may vary when combined with other treatments, like immunotherapy. The efficacy of ADC has been proved in PFS and OS in trials for metastatic breast cancers. Control rates and duration of BMs are much more potent than conventional chemotherapeutic agents. Therefore, achieving a long-term survival impact will be possible, but achieving EFS impact in neoadjuvant trials might be slightly challenging. (III) Toxicity in neoadjuvant and adjuvant settings might be less than that in metastatic breast cancer settings because the performance status of primary breast cancer patients is generally better than that of metastatic breast cancer patients (106). However, we haven’t got enough data to assess the toxicity profile in primary breast cancer patients. Indeed, the general goal of neoadjuvant and adjuvant therapy is to suppress recurrence and prolong survival. Interruption of the treatment due to the toxicity may result in reducing the chance to control the disease. Currently, there is limited knowledge about how stopping or discontinuing ADC treatment impacts the prognosis of patients with primary breast cancer, making this an essential area for future research. (IV) In addition, the assessment of QOL might be key to overview the ADC therapy for primary breast cancer in comparison with conventional chemotherapy (107,108). (V) Costs for ADCs are generally high. In the current situation, a high cost for escalating therapy to improve survival significantly would be acceptable. Still, controversy remains over the appropriate costs to improve QOL. Further detailed discussions are necessary, and this issue may differ by country and region. When ADCs receive approval for primary breast cancer, both global and regional analyses will be essential. (VI) Various translational research studies are being conducted on ADC treatment, especially on discovering clinically available predictive biomarkers and monitoring markers. However, their results are limited at present. Some biomarkers for ADCs, such as HER2-low, are already in use. The main points to consider include epitope expression status, activities related to antibody incorporation and the digestion process, sensitivity and resistance to payload drugs like TOPO-1 inhibitors, and tumour heterogeneity and tumour microenvironment characteristics in relation to the extent of bystander effects. On the other hand, predicting and managing ADC toxicity are critical issues. For preoperative and postoperative treatments, 6 to 8 cycles of administration are typically used. Careful planning and clinical management may help minimize severe toxicities, such as ILD. While the design of clinical trials is essential, ensuring high-quality clinical management in practice is equally important. (VII) Another challenging aspect is the integrated approaches to assess clinical usefulness, patient satisfaction, and cost-effectiveness comprehensively.

Conclusions

ADCs have been regarded as a magnificent treatment tool for improving survival outcomes in metastatic breast cancer patients, regardless of tumour subtype. They are beneficial not only for HER2-positive cancers but also for HER-2-negative ones. Neoadjuvant and adjuvant studies with ADCs are being conducted extensively for most primary breast cancer subtypes. Several neoadjuvant trials have reported preliminary results, and the outlook is generally promising. Regarding the treatment strategy, escalation and de-escalation directions are being investigated. These trials are designed based on an assessment of the recurrence risk of the disease. In part, there are attempts to replace conventional chemotherapies with ADC. Currently, there is limited knowledge about clinically valuable biomarkers for ADCs in primary breast cancer. This highlights the need for more translational research focused on biomarker development. Such advancements are crucial for both therapy escalation and de-escalation strategies. ADCs can be used independently or in combination with other therapies like immunotherapy. In addition to their roles in predicting efficacy and prognosis, developing precise markers for monitoring therapeutic effectiveness is essential. This includes not only blood-based markers but also imaging markers. It is also important to closely investigate how interrupting or discontinuing treatment affects patient prognosis. Moreover, objective evaluation of QOL and patient satisfaction is crucial. These factors should be studied in an integrated approach to optimize ADC treatment, enhance therapeutic efficacy, and minimize therapy-related demerits, including cost-effectiveness. Since medical economic evaluations vary by country, they should be conducted regionally. Overall, despite potential challenges, the application of ADCs in primary breast cancer remains an attractive option. Further research is needed to explore this area comprehensively.

Acknowledgments

I thank Ms. S Suzuki, Ms. M Serizawa and Ms. Hirono Takeda for their kind support.

Footnote

Peer Review File: Available at https://tbcr.amegroups.org/article/view/10.21037/tbcr-25-2/prf

Funding: This work was partially supported by the Special Research Program of the Tokyo Metropolitan Government.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://tbcr.amegroups.org/article/view/10.21037/tbcr-25-2/coif). M.T. serves as an unpaid editorial board member of Translational Breast Cancer Research from December 2023 to November 2025. M.T. has served on advisory boards for Bertis, Daiichi Sankyo, Eli Lilly, Kansai Medical Net, and Terumo; has received compensation as an invited speaker from AstraZeneca, Bertis, Bristol Myers Squibb, Chugai, Devicore Medical Japan, Eisai, Eli Lilly, Exact Science, Kyowa-Kirin, Merck Sharp & Dohme, Nippon-Kayaku, Novartis, Pfizer, Shimadzu, Sysmex, Taiho, Takeda, and Yakult; has received research funding from AFI Technology, Astellas, AstraZeneca, Chugai, Daiichi Sankyo, Eisai, Eli Lilly, GL Science, Kansai Medical Net, Luxonus, Pfizer, Sanwa Shurui, Shimadzu, Takeda, The Japan Breast Cancer Research Group association, The Kyoto Breast Cancer Research Network association, and Yakult; has served on steering committees for AstraZeneca, Daiichi Sankyo, and Eli Lilly; and serves as a member of the board of directors for the Organisation for Oncology and Translational Research, The Japan Breast Cancer Research Group association, The Kyoto Breast Cancer Research Network association, and The Japanese Breast Cancer Society. The author has no other conflicts of interest to declare.

Ethical Statement: The author is 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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