Radiol Oncol 2024; 58(2): 258-267. doi: 10.2478/raon-2024-0030 258 expert opinion Advancing HER2-low breast cancer management: enhancing diagnosis and treatment strategies Simona Borstnar1, Ivana Bozovic-Spasojevic2, Ana Cvetanovic3, Natalija Dedic Plavetic4, Assia Konsoulova5, Erika Matos1, Lazar Popovic6, Savelina Popovska7, Snjezana Tomic8, Eduard Vrdoljak8 1 Institute of Oncology Ljubljana, Slovenia 2 Institute for Oncology and Radiology of Serbia, Medical Faculty, University of Belgrade, Serbia 3 Department of Oncology, Medical Faculty University of Niš; Clinic of Oncology, University Clinical Centre Niš, Serbia 4 University Hospital Centre Zagreb, School of Medicine, University of Zagreb, Croatia 5 National Cancer Hospital, Sofia, Bulgaria 6 Oncology Institute of Vojvodina, Faculty of Medicine, University Novi Sad, Novi Sad, Serbia 7 Medical University Pleven, Bulgaria 8 University Hospital of Split, University of Split - School of Medicine, Croatia Radiol Oncol 2024; 58(2): 258-267. Received 4 January 2024 Accepted 14 May 2024 Correspondence to: Simona Borštnar, M.D., Ph.D., Institute of Oncology Ljubljana, Zaloška 2, SI-1000 Ljubljana, Slovenia. E-mail: sborstnar@ onko-i.si All authors contributed equally to this paper. Disclosure: Simona Borštnar declares support for present manuscript for medical writing and article processing charge from AstraZeneca; consulting fees from AstraZeneca, Eli Lilly, MSD, Novartis, Pfizer, Roche, and Swixx; payment or honoraria for lectures, presentations, speak- ers bureaus, manuscript writing or educational events from AstraZeneca, Gilead, Eli Lilly, MSD, Novartis, and Pfizer. Ivana Božović-Spasojević declares support for present manuscript for medical writing and article processing charge from AstraZeneca; speaker and consulting fees from AstraZeneca, MSD, Novartis, PharmaSwiss, Pfizer, and Roche. Ana Cvetanović declares support for present manuscript for medical writ- ing and article processing charge from AstraZeneca; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events and support from attending meetings and/or travel from AstraZeneca, Eli Lilly, Hemofarm, Merck, MSD, Novartis, Pfizer, and Roche; participation on a Data Safety Monitoring Board or Advisory Board from AstraZeneca, MSD, Novartis, Pfizer, and Roche; and leadership or fiduciary role in other board, society, committee, or advocacy group in Serbian Society of Medical Oncology (Vice President). Natalija Dedić Plavetić declares support for present manuscript for medical writing and article processing charge from AstraZeneca; grants or contracts for clinical trials from Novartis and Roche; consulting fees from AstraZeneca, Novartis, MSD, and Pfizer; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AstraZeneca, Novartis, MSD, Pfizer, and Roche. Erika Matos declares support for present manuscript for medical writing and article processing charge from AstraZeneca; consulting fees from AstraZeneca, Eli Lilly, and MSD; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AstraZeneca; Eli Lilly, MSD, and Novartis. Snježana Tomić declares support for present manuscript for medical writing and article processing charge from AstraZeneca; consulting fees from AstraZeneca, MSD, Novartis, and Roche Oncology; and payment or hono- raria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca, MSD, Novartis, and Roche Oncology; and support for attending meetings and/or travel from AstraZeneca, MSD, and Roche Oncology. Eduard Vrdoljak declares support for present manuscript for medical writing and article processing charge from AstraZeneca; support for clinical trials and scientific projects from AstraZeneca, BMS, Pfizer, and Roche; speaker and consulting fees from Amgen, Astellas, AstraZeneca, Boehringer Ingelheim, Johnson & Johnson, MSD, Merck, Novartis, Pharmaswiss, Pfizer, Roche, and Sanofi. Assia Konsoulova, Savelina Popovska and Lazar Popović declare sup- port for present manuscript for medical writing and article processing charge from AstraZeneca. This is an open access article distributed under the terms of the CC-BY license (https://creativecommons.org/licenses/by/4.0/). Background. Recent evidence brought by novel anti-human epidermal growth factor receptor 2 (HER2) antibody- drug conjugates is leading to significant changes in HER2-negative breast cancer (BC) best practices. A new targeta- ble category termed ‘HER2-low’ has been identified in tumors previously classified as ‘HER2-negative’. Daily practice in pathology and medical oncology is expected to align to current recommendations, but patient access to novel anticancer drugs across geographies might be impeded due to local challenges. Materials and methods. An expert meeting involving ten regional pathology and oncology opinion leaders expe- rienced in BC management in four Central and Eastern Europe (CEE) countries (Bulgaria, Croatia, Serbia, Slovenia) was held. Herein we summarized the current situation of HER2-low metastatic BC (mBC), local challenges, and action plans to prevent delays in patient access to testing and treatment based on expert opinion. Radiol Oncol 2024; 58(2): 258-267. Borstnar S et al. / HER2-low breast cancer: enhancing diagnosis and treatment strategies 259 Introduction In the era of precision medicine, the diagnostic and treatment landscape in oncology has progres- sively become more biomarker driven.1,2 In solid tumors, an early example of biomarkers with pre- dictive value was the human epidermal growth factor receptor 2 (HER2), with positive results predicting response to targeted treatment with anti-HER2 monoclonal antibodies but no benefit for HER2-negative tumors.1 In breast cancer (BC), HER2 overexpression/gene amplification deter- mined by immunohistochemistry (IHC) and/or in situ hybridization (ISH) is found in 15−20% of all tumors.3-5 Anti-HER2-directed therapies have sig- nificantly improved the survival of patients with both early and metastatic HER2-positive BC and consequently changed the treatment paradigm, being accepted as the standard of care through- out the world.5,6 The current pathology guidelines define HER2-positive tumors when the IHC score is 3+ or 2+ with the HER2 encoding gene (erb-b2 receptor tyrosine kinase 2 [ERRB2]) amplification by ISH (ISH-positive), whereas HER2-negative tu- mors have IHC scores of 0+, 1+, or 2+/ISH-negative.7 In light of recent evidence brought by novel an- ti-HER2 antibody-drug conjugates (ADCs)5,8–12, the current knowledge of HER2 expression range and its clinical applicability is changing since a signifi- cant proportion of HER2-negative tumors are in fact characterized by a spectrum of HER2 expres- sion levels.13,14 A new targetable category has been identified in patients whose tumors are scored IHC 1+ or 2+/ISH-negative3, and this low level of HER2 expression has been termed ‘HER2-low’.15 HER2-low status is detected in 45−55% of all BC tu- mors: around two-thirds (65%) in hormone recep- tor-positive (HR+) BC and one-third (36%) in HR- negative (HR-) cancers.6,16 Treatment paradigms for both HR+ and HR- BC with HER2-low expression are evolving at a fast pace, leading to a new ‘revo- lution’.17 The clinical trial DESTINY-Breast04 (DB- 04), evaluating trastuzumab deruxtecan (T-DXd) in patients with HER2-low advanced BC previously treated with chemotherapy, showed significant and clinically meaningful progression-free surviv- al (PFS) and overall survival (OS) improvements and a manageable safety profile as compared with conventional chemotherapy (PFS 10.1 months for T-DXd vs 5.4 months in the physician’s choice of chemotherapy, hazard ratio=0.64, P=0.003, and OS 23.9 months for T-DXd vs 16.8 months in the physi- cian’s choice of chemotherapy, hazard ratio=0.64, P=0.001, respectively).12 These results, together with the other ADC data, demonstrate the clinical relevance of HER2-low expression and are trans- forming the current understanding, and therefore management, of HER2-negative BC.5,8-12,17-20 Despite guideline recommendations for HER2- low diagnosis and European Society for Medical Oncology (ESMO) consensus reached for its treat- ment5,7, implementing guidelines in a real-life set- ting is a lengthy and difficult process, partly due to the diverse accessibility of novel anticancer medi- cines. In countries in Central and Eastern Europe (CEE), significant delays in patient access to inno- vative oncology treatments have been previously described.21-24 In an attempt to avoid such delays with ADCs in HER2-low BC, an expert meeting was held to identify the challenges and local un- met needs, and to find solutions to optimize access to diagnostics and adequate treatment of HER2- low metastatic BC (mBC) for patients from CEE. In this paper, we discuss the current situation per- taining to the overall diagnosis and management of HER2-low mBC and propose potential solutions to address the unmet needs in four CEE countries; we also consider similar situations, and solutions that may apply to many other former or current transitional countries throughout the world. Results. Gaps and differences at multiple levels were identified across the four countries. These included variability in the local HER2-low epidemiology data, certification of pathology laboratories and quality control, and reimbursement conditions of testing and anticancer drugs for HER2-negative mBC. While clinical decisions were aligned to interna- tional guidelines in use, optimal access to testing and innovative treatment was restricted due to significant delays in reimbursement or limitative reimbursement conditions. Conclusions. Preventing delays in HER2-low mBC patient access to diagnosis and novel treatments is crucial to op- timize outcomes. Multidisciplinary joint efforts and pro-active discussions between clinicians and decision makers are needed to improve care of HER2-low mBC patients in CEE countries. Key words: HER2-low; metastatic breast cancer; Balkans; testing; innovative treatment; access Radiol Oncol 2024; 58(2): 258-267. Borstnar S et al. / HER2-low breast cancer: enhancing diagnosis and treatment strategies260 Methods A panel of ten opinion leaders was organized as part of a virtual meeting logistically supported by AstraZeneca and held on June 12, 2023. Eight medical oncologists and two pathologists from academic centers and/or national institutes of on- cology in Bulgaria, Croatia, Serbia, and Slovenia with experience in the diagnosis, management, and follow-up of mBC patients from the CEE re- gion were individually approached and further agreed to participate in the panel discussion. A pre-meeting survey was developed specifically for this project and reviewed by experts. The experts responded in anonymized manner to the prelimi- nary survey, which included 31 questions grouped in the following four topics: epidemiology, biol- ogy, pathologic diagnosis, and treatment of HR (+/-) HER2-low mBC. The average time to fill the survey was around 15 minutes. Data from the sur- vey were retrieved in an excel sheet; all experts re- sponded to the survey, with the difference that the specific treatment questions did not apply to the pathology experts. No formal statistical analysis was used. The responses grouped under the main topics were further discussed in detail during the meeting, while experts agreed that the structure of the manuscript will follow these topics. For each of these, the thought leaders discussed the institu- tional or national data versus literature, described the unmet needs across countries, and shared their independent views and experience. Relevant data discussed in the medical community with regard to the spectrum of the HER2-low in breast cancer were considered to firstly describe the general con- text and then, to a greater extent, elaborate on the local circumstances (no formal literature review). Experts identified local and/or regional challenges and constraints of clinical oncology and pathology daily practice and proposed action plans aimed at improving testing and access to treatment and, consequently, outcomes of HER2-low mBC for pa- tients at the country and CEE level. Results and discussion Epidemiology of HER2-low breast cancer Current status and challenges The four CEE countries represented in this pa- per differ in terms of total population; however, in all four of these countries, BC ranks second or third in prevalence among all types of cancers and is one of the leading causes of death in women (Table 1).25 BC incidence rates remain high in the region and are predicted to increase in the future due to the global trend of an increasingly aging population.26,27 Early detection (eg screening pro- grams) of BC is problematic in countries that have undergone economic transitions like those in CEE; many still lack clear policies and sustained invest- ments in their medical healthcare systems.28 Even so, the mortality-to-incidence ratio (MIR), which is an indicator of healthcare quality, with low values indicating better care (prevention, treatment, and overall management), varies slightly and is similar to the average European value (0.27) in Slovenia and Croatia.29 As compared with data from 201228, we observe decreases in the MIR in all four coun- tries, which might show that advances in cancer TABLE 1. Overview of cancer epidemiology across four CEE countries in 2020 (data extracted from GLOBOCAN 202025 and the European Cancer Information System34) Characteristics Bulgaria Croatia Serbia Slovenia Total population 6 948 445 4 105 268 8 737 370 2 078 932 Number of new cancer cases (all cancer sites) 36 451 26 092 49 043 14 180 Incidence age-standardized rate per 100 000 100 120.3 145.3 121.2 Number of new BC cases in 2020, both sexes, all ages 4061 2894 6724a 1410 BC new cases – rank across all types of cancers 3 2 2 3 5-year prevalence, all ages (per 100 000) 425.45 523.4 549.32 560.03 Mortality age-standardized rate per 100 000 36.3 32.8 50.9 32.3 Number of BC deaths 1533 832 2342 405 BC deaths – rank across all types of cancers 3 3 2 5 Mortality-to-incidence ratiob 0.36 0.27 0.35 0.27 Radiol Oncol 2024; 58(2): 258-267. Borstnar S et al. / HER2-low breast cancer: enhancing diagnosis and treatment strategies 261 care have been made to some extent in the last two decades. Despite these encouraging signs, recent data show trends of increase in BC mortality in Bulgaria and Croatia in women over 45 years.30 In most Eastern European countries, patients with BC have a shorter OS following diagnosis compared with the rest of Europe31; however, in Slovenia, survival has been shown to be increasing over time.32 Multiple challenges and gaps in receiving optimal cancer care by individuals with mBC have been described, especially in underserved patient populations from the CEE region where socio- economic inequalities and educational or cultural status have a considerable impact on the quality of healthcare.33 Compared with reported rates for HER2-low cases, which range between 45% and 65% in HR+ tumors and 23% to 40% in HR- tumors6,16,35, local reports indicate a similar or slightly lower per- centage of HER2-low cases. In a sample of 11 234 cases from the Oncology Institute of Ljubljana (Slovenia), collected from 2011 to 2021, HER2-low (1+/2+ non-amplified) was identified in 52.8% of cases. The rate of HER2 IHC 0 decreased in the last 2 years of follow-up (2020, 2021), whereas the rate of HER2-low increased.36,37 In Croatia, according to the National Pathohistological Breast Registry of newly diagnosed BC patients, in a sample of 8488 patients (early-stage, locally advanced, or meta- static BC), the HER2-low rate in the past 3 years was 42% (44% HER2-low in luminal A cancers, 54% in luminal B, and 36% in triple-negative BC) (unpublished data). In Serbia, in a sample of 500 patients from the Novi Sad registry, HER2-low sta- tus was identified in 50% of cases, irrespective of stage, whereas in mBC patients with testing per- formed only in primary tumors, the rate of HER2- low was 30% (unpublished data). For Bulgaria, no official data are available. Unmet needs Robust, more standardized data on incidence, prevalence, and mortality rates by type and stage of BC, and outcomes in specific groups that are usually underserved (i.e., men, patients with co- morbidities, patients of cultural/racial/religious di- versity) are scarce in the region and, consequently, very much needed. The difference between data from Western countries and those in the CEE re- gion may be partly explained by lack of properly founded national cancer registries and clinical da- tabases collecting systemized oncology data and, of course, variations of the healthcare systems in CEE. Progress has been made recently (for exam- ple, in January 2023 Slovenia opened the Clinical Breast Cancer Registry), and more changes are ex- pected in the future. Action plan We outlined the following top priorities: (1) to extract retrospective data from healthcare re- cords in a centralized way in each country and use them as a benchmark for future studies; (2) to expand existing registries/protocols to in- clude all HER2-low BC patients. These actions would more sufficiently explore the variability across countries and adequately inform diagnosis and management strategies for improving patient care in CEE countries based on recent and reliable real-world evidence. Most importantly, this would aid communication with health authorities to expedite access to effec- tive anticancer drugs for patients in this region. Continuous monitoring and reporting of manage- ment of patients with BC on a national and po- tentially regional or, even better, European level, is necessary to inform healthcare policies and re- forms. Exposing the weaknesses of general health- care and/or oncology systems will help to improve outcomes by addressing similar issues. Biology of HER2-low breast cancer Current status and challenges Whether HER2-low is a distinct biological entity or not is one of the key questions in the field of HER2- low biology.16,38 While the spectrum of HER2 posi- tivity expands, no robust evidence exists to con- sider HER2-low a clinically distinctive entity or a definite subtype14,39,40, which has led some groups to conclude that such categorization remains to be clarified in the future.17,20,41 At a local level, a re- cent report from Serbia including patients with early BC has shown a higher proportion of patho- logic complete response after neoadjuvant chemo- therapy in patients with HER2 IHC 0 as compared with HER2-low, indicating that new and improved treatment modalities are required for HER2-low patients.42 Tumor heterogeneity and tumor plasticity that traditionally characterize breast carcinomas also apply to HER2-expressing tumors.5,43 HER2 intra- tumoral (spatial) heterogeneity is a well-known phenomenon reported in up to 40% of BC.44,45 HER2-low expression was shown to be highly un- stable during disease evolution, with a higher pro- portion of HER2-low rates in recurrent BC samples (temporal heterogeneity).38,46,47 Radiol Oncol 2024; 58(2): 258-267. Borstnar S et al. / HER2-low breast cancer: enhancing diagnosis and treatment strategies262 Other matters of debate in the literature dis- cussed were whether the efficacy of HER2-targeted treatments is higher in tumors with higher HER2 expression levels48,49, and how HER2-low could be an escape mechanism displayed by tumors in case of HR+-directed treatments, leading researchers to believe that most cases of mBC will become HER2- low under the pressure of endocrine therapies.50-52 Unmet needs Re-biopsy availability is related to our understand- ing of HER2-low biology. Yet, there is no specific strategy for re-biopsy at recurrence at the country or regional level, and computed tomography (CT)- guided biopsies are difficult to access and gener- ally rarely performed. While financing for re-bi- opsies may not be an issue, Serbia, for example, is hindered by a scarcity of experts who can perform biopsies, such as interventional radiologists or pul- monologists. Action plan To optimize the management and subsequently the outcomes of HER2-low BC patients in future and to address spatial and temporal tumor hetero- geneity, we proposed to: (1) Foster HER2-low early diagnosis by developing and implementing local pathways for mBC pa- tients, with mandatory checks of previous pa- thology reports; (2) perform multiple rounds of re-biopsy at each relapse of locoregional or distant metastases; (3) keep clinicians informed of new treatment op- tions available in their countries, based on a possible different result of the re-biopsy com- pared with the primary tumor biopsy. Pathologic diagnosis of HER2-low breast cancer Current status and challenges Historically, HER2 expression was classified in a binary way: positive or negative.44,53 New evidence indicates that patients with low HER2 expression (IHC 1+ or 2+ and ISH-negative) represent a new targetable category of BC.3 In light of these chang- es, HER2 testing and reporting has become more complex.54 The 2023 updated guidelines issued by the American Society of Clinical Oncology (ASCO)/ College of American Pathologists (CAP) for HER2 testing include no changes in prior (2018) terminol- ogy or traditional terminology of positive/equivo- cal/negative for HER2 IHC results but calls to in- creased awareness for IHC 1+ or 2+ non-amplified cases that deem patients eligible for treatment with T-DXd.7,53 While pathology groups state that HER2- low is a qualitative term55, medical oncologists use conflicting terminology for interpreting ASCO/ CAP guidelines (i.e., HER2-0 with potential future categories HER2-null and HER2-ultralow, HER2- low, HER2-positive).5 Pathology experts agreed that HER2-low is rather an operational term, with ASCO/CAP guidelines being currently followed in pathology clinical practice. No HER2-low term is currently included in reports; however, the term HER2-negative is recommended to be changed in “HER2-negative for protein overexpression/gene amplification” since non-overexpressed levels of the HER2 protein may be present in these cases. Another challenge is related to the compan- ion diagnostic tests for evaluating 1+ and 2+/ISH- negative disease.3 Assays used are either those ap- proved and currently available on the market (with Ventana HER2/neu 4B5 [F. Hoffmann-La Roche Ltd] being more frequently used in the CEE area) or ones developed in-house. Besides temporal and spatial tumor heterogeneity, many other factors are known to impact the IHC scoring – from pre- and post-analytical factors to test sensitivity, type of specimen, and laboratory and/or reader experi- ence.3,6,56-58 Among the specific pathology challenges men- tioned at local level, the following were under- lined: in Bulgaria, lack of reimbursement for ISH (ISH tests are paid for by patients), lack of continu- ous medical education for pathologists to train on the changing paradigm of HER2 assessment, reporting and its relevance to treatment, lack of certification process of either pathology labora- tories or clinical centers, and no quality control processes in place. In Serbia, previous discord- ance in IHC detection of HER2 between national pathology laboratories was reported (the overall agreement ranged between 79% and 89%), with discrepancies on chromogenic ISH indicating a misdiagnosis rate of almost 16%.59 In Croatia, in a sample of 126 patients, discordance in HER2 scor- ing between central and local laboratories was 12% – results that are in line with the literature.60,61 The sources of error in the local study were partly pre- analytical and partly analytical, thus emphasizing the need for rigorous application of standardized staining and scoring procedures for precise deter- mination of HER2 protein level, which is particu- larly important in the HER2-low group. The ex- perts from Bulgaria added that a high variability of HER2 testing results between pathology centers Radiol Oncol 2024; 58(2): 258-267. Borstnar S et al. / HER2-low breast cancer: enhancing diagnosis and treatment strategies 263 also applies in their country, leading to high num- ber of retesting and second opinions. Unmet needs In terms of pathology diagnosis, the unmet needs identified in the four countries from the CEE re- gion are broad and at multiple levels: specific med- ical education for pathologists, reimbursement of ISH testing in all countries, improved robustness of HER2 testing with current available techniques, standardization of and quality-controlled HER2 testing between centers, precise and accurate re- porting systems, more homogenous inter-institu- tional procedures, and more certified laboratories. Action plan The action plan discussed included the following proposals: (1) to improve pre-analytical and analytical phases of HER2 testing and to reduce false-negative/ false-positive reports, a rigorous internal and external quality control is required at every in- stitutional level; (2) to increase awareness of HER2-low testing and scoring and to improve reporting, virtual meet- ings, and live workshops for pathology special- ists, as well as multidisciplinary meetings of all specialists involved in the management of HER2-low BC patients, should be formally or- ganized in each country; (3) to improve HER2-low score accuracy and re- duce inter-laboratory variability, participation in ring studies is highly encouraged; (4) to increase comparability across various geog- raphies and build best practices, center-, coun- try-, and regional-level monitoring and report- ing of pathology results is recommended. Treatment of HER2-low breast cancer Current status and challenges CEE countries are characterized by a variable re- imbursement status of anticancer drugs for HER2- negative mBC (Table 2). In Slovenia the majority of treatments are reimbursed, irrespective of line of treatment; however, T-DXd is not yet reimbursed for HER2-low BC. In Croatia, despite innovative treatments being reimbursed, their use in later line (third line [3L]+) depends on budgetary decisions at the institutional level, potentially introducing disparity in the treatment of mBC patients in need. By contrast, in Bulgaria, reimbursement is granted in general in any line for all drugs approved at the European level for HER2-positive mBC, which fa- cilitates treatment sequencing; however, this does not apply for HER2-low mBC. Serbia faces the big- gest challenges in the region, with innovative drugs being available for first-line (1L) and second-line (2L)/3L HER2-positive mBC, while treatment op- tions for metastatic triple-negative and HR+ BC are TABLE 2. Status of reimbursement for anticancer drugs used for treatment of HER2-negative mBC in Bulgaria, Croatia, Serbia, and Slovenia, including the year of reimbursement of at least one representative of the class Treatment Bulgariaa Croatia Serbiac Sloveniad CDK4/6 inhibitors 2018 2018 2022 2018 Alpelisib 2023 2021 2023 2021 PARP inhibitors 2023 2022 2021 2021 Sacituzumab govitecan 2023 2022 Trastuzumab deruxtecan 2022 2023 Atezolizumab nab-paclitaxel 2022 2021 2020 Pembrolizumab 2023b 2022 2023 Everolimus By >10 years 2021 2010 Fulvestrant By >10 years By >10 years 2019 2004 Aromatase inhibitors By >10 years By >10 years 2008 By >20 years Green = reimbursed; orange = not reimbursed, but available through early access programs or out-of-pocket expenses; red = not reimbursed; CDK4/6 = cyclin-dependent kinase 4 and 6; HER2 = human epidermal growth factor receptor 2; mBC = metastatic breast cancer; PARP = poly(adenosine diphosphate ribose) polymerase; aIn Bulgaria, PARP inhibitors are available in early breast cancer and BRCA-positive tumors after lack of complete response in the neoadjuvant setting. In the metastatic setting, PARP inhibitors have been reimbursed since 2019, everolimus is reimbursed in metastatic estrogen receptor-positive (ER+) BC, and aromatase inhibitors are reimbursed in ER+ BC; b In Bulgaria, pembrolizumab is reimbursed only in triple-negative BC within HER2-negative BC; c In Serbia, medications in orange are registered and could be used in special circumstances but are not reimbursed/covered by public health insurance for HER2-negative mBC; d In Slovenia, sacituzumab govitecan is reimbursed for triple-negative BC only, and trastuzumab deruxtecan for HER2-positive BC only. Radiol Oncol 2024; 58(2): 258-267. Borstnar S et al. / HER2-low breast cancer: enhancing diagnosis and treatment strategies264 being limited. For example, only cyclin-dependant kinase 4 and 6 (CDK4/6) inhibitors as innovative medicines are being reimbursed in 1L and 2L for HR+ mBC. By contrast, alpelisib, poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors, and the ADCs sacituzumab govitecan and T-DXd can be approved in some specific circumstances, but only in later lines when other therapy options are exhausted. In consequence, the meaningful clinical applicability of the drug is significantly decreased, because rates of treatment success in later lines are rather small. In all four CEE countries, the ESMO guidelines and, in some countries, local guidelines with ap- plicable updates are followed.62-64 Whereas treat- ment decisions in 1L are aligned across countries, experts agreed that decisions in 2L/3L are individ- ualized based on patient and tumor characteristics and treatment outcomes, although these decisions are highly dependent on reimbursement condi- tions. While innovative treatments are usually ap- proved in Europe through a centralized procedure via the European Medicines Agency65, the high costs of new anticancer drugs restrict their use until reimbursement. Previous reports from CEE have shown significant delays from marketing authorization to reimbursement of novel oncol- ogy medicines and reduced numbers of available drugs in this region, which undoubtedly leads to worsening patient outcomes.21,24,66 For example, perhaps due to diverse reimbursement models and policies and lack of sustained investment in the oncology field, trastuzumab, one of the essential medicines for treatment of HER2-positive BC, did not receive full reimbursement in Eastern Europe and, with the exception of Slovenia and Croatia, was insufficiently procured to allow treatment ac- cess to all patients in need for several years.22,23,28 We have identified the following challenges applicable, to various extents, in all participating countries: significant delays in reimbursement de- cisions; limitative, restrictive reimbursement con- ditions that impact sequencing and/or treatment rechallenges; limited access to clinical trials with novel cancer medicines; and early access/bridg- ing programs until treatment reimbursement. In addition, optimal sequencing remains to be deter- mined, as levels of evidence are variable for differ- ent treatments. Unmet needs Unmet needs of equal importance for adequate access to treatment of HER2-low mBC were avail- ability and/or full reimbursement of treatments 1L 2L 3L 4L BRCAwt PI3Kwt ET±CDK4/6i ET±mTORi CTx CTx T-DXd ET±mTORi T-DXd CTx ET±mTORi BRCAm PI3Kwt ET±CDK4/6i PARPiET±mTORi CTx PARPi T-DXd ET±mTORi ET±mTORiT-DXd CTx ET±mTORiPARPi BRCAwt PI3Km ET±CDK4/6i CTx T-DXd ET±alpelisib ET±mTORi or CTx T-DXd ET±mTORi CTx ET±alpelisib BRCAm PI3Km ET±CDK4/6i CTx ET±alpelisib T-DXd PARPi ET±mTORi ET±alpelisib PARPi ET±alpelisib CTx PARPi T-DXd 1L 2L 3L 4L BRCAwt PD-L1+ IO ± CTx T-DXd T-DXd SG CTx BRCAwt PD-L1- T-DXd BRCAm PD-L1+ IO + CTx SG T-DXd CTx T-DXd SGPARPi BRCAm PD-L1- PARPi CTx SG Other CTx T-DXd SG CTx Other PARPi IO + CTx T-DXd CTx SG T-DXd CTx PARPi HR+ HR- A B FIGURE 1. Algorithms for HER2-low mBC in light of evolving treatment paradigms, according to the HR status and other actionable targets: (A) HR+ and (B) HR-. The ideal scenario considers availability of all treatments in all lines and unrestricted treatment access. 1L/2L/3L/4L = first/second/third/fourth line; BRCAm = BReast CAncer gene mutations; BRCAwt = BReast CAncer gene wild type; CDK4/6i = cyclin-dependent kinase 4/6 inhibitor; CTx = chemotherapy; ET = endocrine therapy; HER2 = human epidermal growth factor receptor 2; HR = hormone receptor; IO = immunotherapy; mBC = metastatic breast cancer; mTORi = mammalian target of rapamycin inhibitor; PARPi = poly(adenosine diphosphate ribose) polymerase inhibitor; PD-L1 = programmed death-ligand 1; PI3Km = phosphatidylinositol 3-kinases mutations; PIK3wt = phosphatidylinositol 3-kinases wild type; SG = sacituzumab govitecan; T-DXd = trastuzumab deruxtecan. Treatment in 2L, 3L, 4L, and further lines is based on: previous therapy received; duration of response to previous treatment; patient’s preferences, condition, and comorbidities; toxicities of previous therapies; presumed benefit of further lines of therapy; and treatment availability. Per current approved label, trastuzumab deruxtecan as monotherapy is indicated for the treatment of adult patients with unresectable or metastatic HER2-low breast cancer who have received prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy. Per current approved label, sacituzumab govitecan as monotherapy is indicated for the treatment of adult patients with unresectable or metastatic triple-negative BC who have received two or more prior systemic therapies, including at least one of them for advanced disease. Radiol Oncol 2024; 58(2): 258-267. Borstnar S et al. / HER2-low breast cancer: enhancing diagnosis and treatment strategies 265 in all lines, extension of reimbursement criteria to all lines of treatment for medicines with mar- keting authorization granted, and reduced times from product marketing authorization to reim- bursement for novel, innovative anticancer drugs. Avoiding repeating the situation of trastuzumab reimbursement and ensuring active involvement of all stakeholders in cancer care are prerequisites for preventing disparities in treatment of HER2- low BC patients between CEE countries. Action plan Key actions for optimizing access to HER2-low BC treatments are summarized below: (1) While changing the reimbursement models at country level is beyond the scope of this initia- tive, the experts propose a treatment algorithm for HER2-low mBC aligned to the current evi- dence, guidelines, and clinical practice, accord- ing to HR status and other actionable targets, provided there is no limited access to treat- ments, including availability in all lines, and patients are not in visceral crisis (Figure 1). (2) To prevent delays or lack of any patient access to treatments proven to prolong survival, a clear process mapping of the HER2-low mBC patient journey is strongly advised. Permanent commu- nication with local decision authorities at every level and on multiple channels should be initi- ated by the medical community and supported by up-to-date and sound evidence of treatment benefits. For example, lobbying for alignment to ESMO-Magnitude of Clinical Benefit Scale (MCBS) for fast approval and reimbursement in the CEE area for drugs with scores of 4 and 5 would provide authorities with additional doc- umentation and a reproducible methodology to assess the magnitude of the benefits ensured by novel anticancer drugs.67 In addition, involving patient organizations to advocate change poli- cies to improve access to medicines and cancer outcomes is needed. Although the actual role played by patient representatives across each country is less known and expected to vary, their inclusion into the open dialogue with the authorities should be encouraged and support- ed by clinicians. Conclusions This paper presents the opinions of oncology and pathology experts from four CEE countries on the optimal management of HER2-low mBC. Existing barriers to rapid diagnosis were identified, and treatment choices were proposed for real-world settings. Gaps and differences in the local epide- miology data on HER-2 low BC, certification of pathology laboratories and quality control, and availability of anticancer drugs for HER2-negative mBC across the CEE countries were identified. Preventing delays in HER2-low mBC patient ac- cess to diagnosis and timely and as-per guidelines therapies is crucial to improve outcomes. Pathology reports should no longer report bi- nary results as HER2-positive or -negative but in- clude (ideally) the category of HER2-low and detail the positive score through the number of “+” be- cause this is now becoming critical for treatment decisions. Clinicians should have pro-active dis- cussions with policymakers and stakeholders, in- cluding patients and their representatives, in order to enable advances in HER2-low mBC diagnosis and treatment to truly optimize patient outcomes in the CEE region. Acknowledgments This initiative received no external funding, but medical writing support and the article processing charge were funded by AstraZeneca. The authors would like to thank Ivana Magdić Blažević and Tina Jerič from AstraZeneca for pro- ject management and providing support in organ- izing the Expert Meeting. Medical writing support in drafting the manuscript and revising to ad- dress author feedback was provided by Ana Maria Iordan, MD, MSc of MedInteractiv (Bucharest, Romania) and was funded by AstraZeneca in ac- cordance with Good Publication Practice (GPP) guidelines (https://www.ismpp.org/gpp-2022). References 1. Schwartzberg L, Kim ES, Liu D, Schrag D. Precision Oncology: who, how, what, when, and when not? Am Soc Clin Oncol Educ Book 2017; 37: 160-9. doi: 10.1200/EDBK_174176 2. Schettini F, Prat A. Dissecting the biological heterogeneity of HER2-positive breast cancer. Breast 2021; 59: 339-50. doi: 10.1016/j.breast.2021.07.019 3. Yang C, Brezden-Masley C, Joy AA, Sehdev S, Modi S, Simmon C, et al. Targeting HER2-low in metastatic breast cancer: an evolving treatment paradigm. Ther Adv Med Oncol 2023; 15: 1-19. doi: 10.1177/17588359231175440 4. DeSantis CE, Ma J, Gaudet MM, Newman LA, Miller KD, Saurer AG, et al. Breast cancer statistics, 2019. CA Cancer J Clin 2019; 69: 438-51. doi: 10.3322/caac.21583 5. Tarantino P, Viale G, Press MF, Hu X, Penault-Llorca F, Bardiat A, et al. ESMO expert consensus statements (ECS) on the definition, diagnosis, and management of HER2-low breast cancer Ann Oncol 2023; 34: 645-59. doi: 10.1016/j.annonc.2023.05.008 Radiol Oncol 2024; 58(2): 258-267. Borstnar S et al. / HER2-low breast cancer: enhancing diagnosis and treatment strategies266 6. Tarantino P, Hamilton E, Tolaney SM, Cortes J, Morganti S, Ferraro E, et al. HER2-Low breast cancer: pathological and clinical landscape. J Clin Oncol 2020; 38: 1951-62. doi: 10.1200/JCO.19.02488 7. Wolff AC, Somerfield MR, Dowsett M, Hammond MEH, Hayes DF, McShane LM, et al. Human epidermal growth factor receptor 2 testing in breast can- cer: ASCO–College of American Pathologists Guideline Update. J Clin Oncol 2023; 41: 3867-72. doi: 10.1200/jco.22.02864 8. Banerji U, van Herpen CML, Saura C, Thistlethwaite F, Lord S, Moreno V, et al. Trastuzumab duocarmazine in locally advanced and metastatic solid tumours and HER2-expressing breast cancer: a phase 1 dose-escalation and dose-expansion study. Lancet Oncol 2019; 20: 1124-35. doi: 10.1016/S1470- 2045(19)30328-6 9. Wang J, Liu Y, Zhang Q, Feng J, Chen X, Han Y, et al. RC48-ADC, a HER2- targeting antibody-drug conjugate, in patients with HER2-positive and HER2-low expressing advanced or metastatic breast cancer: a pooled analysis of two studies. [abstract]. J Clin Oncol 2021; 39(15 Suppl): 1022. doi: 10.1200/JCO.2021.39.15_suppl.1022 10. Xu B, Wang J, Fang J, Chen X, Han Y, Li Q, et al. Abstract PD4-06: early clinical development of RC48-ADC in patients with HER2 positive metastatic breast cancer. [abstract]. San Antonio Breast Cancer Symposium; December 10-14, 2019; San Antonio, Texas, 2019 Dec 10-14. Cancer Res 2020; 80(4 Suppl): PD4-06. doi: 10.1158/1538-7445.SABCS19-PD4-06 11. Corti C, Giugliano F, Nicolò E, Ascione L, Curigliano G. Antibody-drug con- jugates for the treatment of breast cancer. Cancers 2021; 13: 1-23. doi: 10.3390/cancers13122898 12. Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E, et al. Trastuzumab deruxtecan in previously treated HER2-Low advanced breast cancer. N Engl J Med 2022; 387: 9-20. doi: 10.1056/nejmoa2203690 13. Holthuis EI, Vondeling GT, Kuiper JG, Dezentje V, Rosenlund M, Overbeek JA, et al. Real-world data of HER2-low metastatic breast cancer: a pop- ulation based cohort study. Breast 2022; 66: 278-84. doi: 10.1016/j. breast.2022.11.003 14. Venetis K, Crimini E, Sajjadi E, Corti C, Guerino-Rocco E, Viale G, et al. HER2 Low, ultra-low, and novel complementary biomarkers: expanding the spec- trum of HER2 positivity in breast cancer. Front Mol Biosci 2022; 9: 1-12. doi: 10.3389/fmolb.2022.834651 15. Schlam I, Tolaney SM, Tarantino P. How I treat HER2-low advanced breast cancer. Breast 2023; 67: 116-23. doi: 10.1016/j.breast.2023.01.005 16. Schettini F, Chic N, Brasó-Maristany F, Pare L, Pascual T, Conte B, et al. Clinical, pathological, and PAM50 gene expression features of HER2-low breast cancer. NPJ Breast Cancer 2021; 7: 1. doi: 10.1038/s41523-020- 00208-2 17. Nicolò E, Boscolo Bielo L, Curigliano G, Tarantino P. The HER2-low revolution in breast oncology: steps forward and emerging challenges. Ther Adv Med Oncol 2023; 15: 1-16. doi: 10.1177/17588359231152842 18. Rassy E, Rached L, Pistilli B. Antibody drug conjugates targeting HER2: clini- cal development in metastatic breast cancer. Breast 2022; 66: 217-26. doi: 10.1016/j.breast.2022.10.016 19. Ferraro E, Drago JZ, Modi S. Implementing antibody-drug conjugates (ADCs) in HER2-positive breast cancer: state of the art and future directions. Breast Cancer Res 2021; 23: 84. doi: 10.1186/s13058-021-01459-y 20. Popović M, Silovski T, Križić M, Dedić Plavetić N. HER2 Low breast cancer: a new subtype or a trojan for cytotoxic drug delivery? Int J Mol Sci 2023; 24: 8206. doi: 10.3390/ijms24098206 21. Newton M, Scott K, Troein P. EFPIA Patients W.A.I.T. indicator 2021 survey. [internet]. IQVIA; 2022. [cited 2023 Dec 15]. Available at: https://www.ef- pia.eu/media/676539/efpia-patient-wait-indicator_update-july-2022_final. pdf 22. Ades F, Senterre C, Zardavas D, De Azambuja E, Popescu R, Piccart M. Are life-saving anticancer drugs reaching all patients? Patterns and discrepan- cies of trastuzumab use in the European Union and the USA. PLoS One 2017; 12: 1-11. doi: 10.1371/journal.pone.0172351 23. Trapani D, Curigliano G, Eniu A. Breast cancer: reimbursement policies and adoption of new therapeutic agents by national health systems. Breast Care 2019; 14: 373-81. doi: 10.1159/000502637 24. Hofmarcher T, Szilagyiova P, Gustafsson A, Dolezal T, Rutkowski P, Baxter C, et al. Access to novel cancer medicines in four countries in Central and Eastern Europe in relation to clinical benefit. ESMO Open 2023; 8: 101593. doi: 10.1016/j.esmoop.2023.101593 25. International Agency for Research on Cancer, World Health Organization. Breast cancer. Population Fact Sheets. [internet]. 2021. [cited 2023 Dec 16] Available at: https://gco.iarc.fr/today/fact-sheets-populations 26. Arnold M, Morgan E, Rumgay H, Mafra A, Singh D, Laversanne M, et al. Current and future burden of breast cancer: Global statistics for 2020 and 2040. Breast 2022; 66: 15-23. doi: 10.1016/j.breast.2022.08.010 27. Vrdoljak E, Bodoky G, Jassem J, Popescu RA, Mardiak J, Pirker P, et al. Cancer control in central and eastern europe: current situation and recom- mendations for improvement. Oncologist 2016; 21: 1183-90. doi: 10.1634/ theoncologist.2016-0137 28. Vrdoljak E, Bodoky G, Jassem J, Popescu R, Pirker R, Čufer T, et al. Expenditures on oncology drugs and cancer mortality-to-incidence ratio in central and Eastern Europe. Oncologist 2019; 24: e30-7. doi: 10.1634/ theoncologist.2018-0093 29. Azadnajafabad S, Saeedi Moghaddam S, Mohammadi E, Delazar S, Rashedi S, Baradaran HR, et al. Patterns of better breast cancer care in countries with higher human development index and healthcare expenditure: insights from GLOBOCAN 2020. Front Public Heal 2023; 11: 1137286. doi: 10.3389/ fpubh.2023.1137286 30. Koczkodaj P, Sulkowska U, Gotlib J, Mańczuk M. Breast cancer mortality trends in Europe among women in perimenopausal and postmenopausal age (45+). Arch Med Sci 2020; 16: 146-56. doi: 10.5114/aoms.2019.85198 31. Allemani C, Matsuda T, Di Carlo V, Harewood R, Matz M, Nikšič, et al. Global surveillance of trends in cancer survival 2000-14 (CONCORD-3): analysis of individual records for 37 513 025 patients diagnosed with one of 18 cancers from 322 population-based registries in 71 countries. Lancet 2018; 391: 1023-75. doi: 10.1016/S0140-6736(17)33326-3 32. Zadnik V, Zagar T, Lokar K, Tomsic S, Konjevic AD, Zakotnik B. Trends in population-based cancer survival in Slovenia. Radiol Oncol 2021; 55: 42-9. doi: 10.2478/raon-2021-0003 33. Vrdoljak E, Gligorov J, Wierinck L, Conte PF, Dr Greve J, Meunier F, et al. Addressing disparities and challenges in underserved patient populations with metastatic breast cancer in Europe. Breast 2021; 55: 79-90. doi: 10.1016/j.breast.2020.12.005 34. ECIS - European cancer information system. Cancer Factsheets in EU-27 countries - 2020. Estimates of cancer incidence and mortality in 2020. Joint research centre. 2020. Available at: https://ecis.jrc.ec.europa.eu/ 35. Gampenrieder SP, Rinnerthaler G, Tinchon C, Petzer A, Balic M, Heibl S, et al. Landscape of HER2-low metastatic breast cancer (MBC): results from the Austrian AGMT_MBC-Registry. Breast Cancer Res 2021; 23: 1-9. doi: 10.1186/s13058-021-01492-x 36. Drev P, Blatnik O, Blazina J, Contreras J, Gašljević G, et al. [Determinations on 15,184 consecutive samples from the Oncology Institute in the period 2006 to 2021]. [Slovenian]. [internet]. 2021. p. 169-70. Available at: https://dirros. openscience.si/Dokument.php?id=21665&lang=slv 37. Auprih M, Gazic B, Drev P, Borstnar S. The frequency of HER2-low breast cancer among patients diagnosed at the Institute of Oncology Ljubljana from 2011 to 2021. Fourth Regional Congress of Medical Oncology - REKONIO 2023. Ljubljana, 2023 Sep 7-9. In: Regional Congress of Medical Oncology REKONIO; 2023. p. 63-4. Ljubljana: Slovenian Medical Association- Section for Medical Oncology, Oncology Institute of Ljubljana, REKOG. Available at: https://rekogconference.com 38. Bergeron A, Bertaut A, Beltjens F, Charon-Barra C, Amet A, Jankowski C, et al. Anticipating changes in the HER2 status of breast tumours with disease progression − towards better treatment decisions in the new era of HER2- low breast cancers. Br J Cancer 2023; 129: 1-13. doi: 10.1038/s41416-023- 02287-x 39. Dieci MV, Miglietta F. HER2: a never ending story. Lancet Oncol 2021; 22: 1051-52. doi: 10.1016/S1470-2045(21)00349-1 40. Polidorio N, Veeravalli SS, Montagna G, Le T, Morrow M. Do HER2 low tumors have a distinct clinicopathologic phenotype? [abstract]. J Clin Oncol 2023; 41(16 Suppl): 570. doi: 10.1200/jco.2023.41.16_suppl.570 41. Rugo HS, Wolf DM, Yau C, Petricoin E, Pohlmann PR, Pusztai L, et al. Correlation of HER2 low status in I-SPY2 with molecular subtype, response, and survival. [abstract]. J Clin Oncol 2023; 41(16 Suppl): 514. doi: 10.1200/ jco.2023.41.16_suppl.514 Radiol Oncol 2024; 58(2): 258-267. Borstnar S et al. / HER2-low breast cancer: enhancing diagnosis and treatment strategies 267 42. Djurmez O, Calamac M, Stanic N, Dimitrijevic M, Vukosavljevic J, Serovic K, et al,.Pathological complete response after neoadjuvantchemotherapy in patients with HER2 low and HER2 0 early breast cancer (eBC) experience from Insititute for Oncology and Radiology of Serbia (IORS). [abstract]. 18th St.Gallen International Breast Cancer Conference. 2023 Mar 15-18, Vienna, Austria. Breast 2023; 68(Suppl 1): S64. Available at: https://breast- ibcc-2023.elsevierdigitaledition.com/63/#zoom=true 43. Lüönd F, Tiede S, Christofori G. Breast cancer as an example of tumour heterogeneity and tumour cell plasticity during malignant progression. Br J Cancer 2021; 125: 164-75. doi: 10.1038/s41416-021-01328-7 44. Marchiò C, Annaratone L, Marques A, Casorzo L, Berrino E, Sapino A. Evolving concepts in HER2 evaluation in breast cancer: heterogeneity, HER2-low carcinomas and beyond. Semin Cancer Biol 2021; 72: 123-35. doi: 10.1016/j.semcancer.2020.02.016 45. Hou Y, Nitta H, Li Z. HER2 intratumoral heterogeneity in breast cancer, an evolving concept. Cancers 2023; 15: 1-12. doi: 10.3390/cancers15102664 46. Bar Y, Dedeoglu AS, Fell GG, Moffett NJ, Bovraz B, Ly A, et al. Dynamic HER2- low status among patients with triple negative breast cancer (TNBC): the impact of repeat biopsies. [abstract]. J Clin Oncol 2023; 41(16 Suppl): 1005. doi: 10.1200/JCO.2023.41.16_suppl.1005 47. Miglietta F, Griguolo G, Bottosso M, Giarratano T, Mele ML, Fassan M, et al. Evolution of HER2-low expression from primary to recurrent breast cancer. NPJ Breast Cancer 2021; 7: 137. doi: 10.1038/s41523-021-00343-4 48. Mosele MF, Lusque A, Dieras V, Ducoulombier A, Pistilli B, Bachelot T, et al. LBA1 Unraveling the mechanism of action and resistance to trastu- zumab deruxtecan (T-DXd): biomarker analyses from patients from DAISY trial. [abstract]. Ann Oncol 2022; 33(Suppl 3): S123. doi: 10.1016/j.an- nonc.2022.03.277 49. Diéras V, Deluche E, Lusque A, Pistilli B, Bachelot T, Pierga JY, et al. Trastuzumab deruxtecan (T-DXd) for advanced breast cancer patients (ABC), regardless HER2 status: a phase II study with biomarkers analysis (DAISY). [abstract]. SABCS 2021 San Antonio Breast Cancer Symposium, 2022 Feb 15. Cancer Res 2022; 82(4 Suppl): PD8-02. doi: 10.1158/1538-7445.SABCS21- PD8-02 50. Mazumder A, Shiao S, Haricharan S. HER2 activation and endocrine treat- ment resistance in HER2-negative breast cancer. Endocrinol 2021; 162: 1-18. doi: 10.1210/endocr/bqab153 51. Pegram M, Jackisch C, Johnston SRD. Estrogen/HER2 receptor crosstalk in breast cancer: combination therapies to improve outcomes for patients with hormone receptor-positive/HER2-positive breast cancer. NPJ Breast Cancer 2023; 9: 45. doi: 10.1038/s41523-023-00533-2 52. Swain SM, Shastry M, Hamilton E. Targeting HER2-positive breast cancer: advances and future directions. Nat Rev Drug Discov 2023; 22: 101-26. doi: 10.1038/s41573-022-00579-0 53. Wolff AC, Elizabeth Hale Hammond M, Allison KH, Harvey BE, Mangu PB, Bartlett JM, et al. Human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology / College of American Pathologists Clinical Practice Guideline focused update. J Clin Oncol 2018; 36: 2105-22. doi: 10.1200/JCO.2018.77.8738 54. Sajjadi E, Guerini-Rocco E, De Camilli E, Pala O, Mazzarol G, Venetis K, et al. Pathological identification of HER2-low breast cancer: tips, tricks, and troubleshooting for the optimal test. Front Mol Biosci 2023; 10: 1-6. doi: 10.3389/fmolb.2023.1176309 55. Schnitt SJ, Tarantino P, Collins LC. The American Society of Clinical Oncology – College of American Pathologists Guideline update for human epidermal growth factor receptor 2 testing in breast cancer: how low can HER2 go? Arch Pathol Lab Med 2023; 147: 991-2. doi: 10.5858/arpa.2023-0187-ed 56. Ahn S, Woo JW, Lee K, Park SY. HER2 status in breast cancer: changes in guidelines and complicating factors for interpretation. J Pathol Transl Med 2020; 54: 34-44. doi: 10.4132/jptm.2019.11.03 57. Fernandez AI, Liu M, Bellizzi A, Brock J, Fadale O, Hanley K, et al. Examination of low ERBB2 protein expression in breast cancer tissue. JAMA Oncol 2022; 8: 1-4. doi: 10.1001/jamaoncol.2021.7239 58. Zaakouk M, Quinn C, Provenzano E, Boyd C, Callagy G, Elsheikh S, et al. Concordance of HER2-low scoring in breast carcinoma among expert pa- thologists in the United Kingdom and the republic of Ireland – on behalf of the UK National Coordinating Committee for Breast Pathology. Breast 2023; 70: 82-91. doi: 10.1016/j.breast.2023.06.005 59. Ivkovic-Kapic T, Knezevic-Usaj S, Moldvaji E, Jovanic I, Milovanovic Z, Milantijevic M, et al. Interlaboratory concordance in HER2 testing: results of a Serbian ring-study. J BUON 2019; 24: 1045-53. PMID: 31424659 60. Jonjić N, Mustać E, Tomić S, Jakić Razzumović J, Sarcević B, Blazicević, et al. Interlaboratory concordance in HER-2 positive breast cancer. Acta Clin Croat 2015; 54: 479-84. PMID: 27017723 61. Roche PC, Suman VJ, Jenkins RB, Davidson NE, Martino S, Kaufman PA, et al. Concordance between local and central laboratory HER2 testing in the breast intergroup trial N9831. J Natl Cancer Inst 2002; 94: 855-7. doi: 10.1093/jnci/94.11.855 62. Gennari A, André F, Barrios CH, Cortes J, de Azambuja E, DeMichele A, et al. ESMO Clinical Practice Guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer Ann Oncol 2021; 32: 1475-95. doi: 10.1016/j.annonc.2021.09.019 63. Curigliano G, Castelo-Branco, L Gennari A, Harbeck N, Criscitiello C, Trapani D on behalf of the CPG author group. ESMO Metastatic Breast Cancer Living Guideline, v1.1 May 2023. [internet]. [cited 2023 Dec 17]. Available at: https://www.esmo.org/living-guidelines/esmo-metastatic-breast-cancer- living-guideline 64. Lovasić IB, Koretić MB, Podolski P, Dedić Plavetić N, Silovski T, Pleština S, et al. [Clinical guidelines for diagnosis, treatment and monitoring of patients with invasive breast cancer – Croatian Oncology Society (BC-3 COS)]. [Croatian]. Liječ Vjesn 2022; 144: 295-305. doi: 10.26800/LV-144-9-10-2 65. European Medicines Agency. From laboratory to patient - the journey of a medicine assessed by EMA. [internet]. Eur Med Agency 2019. [cited 2023 Dec 18]. Available at: https://www.ema.europa.eu/en/documents/other/ laboratory-patient-journey-centrally-authorised-medicine_en.pdf 66. Cufer T, Ciuleanu TE, Berzinec P, Galffy G, Jakopovic M, Jassem J, et al. Access to novel drugs for non-small cell lung cancer in Central and Southeastern Europe: a Central European Cooperative Oncology Group analysis. Oncologist 2020; 25: e598-601. doi: 10.1634/theoncologist.2019-0523 67. ESMO. ESMO-MCBS Scorecards. Scorecards for solid tumors. [internet]. [cited 2023 Dec 19]. Available at: https://www.esmo.org/guidelines/esmo- mcbs/esmo-mcbs-for-solid-tumours/esmo-mcbs-scorecards