Prolonged survival in a HER2 positive metastatic breast cancer patient with brain metastases treated with TDM1 after failure of next generation HER2 targeted therapies

Prolonged survival in a HER2 positive metastatic breast cancer patient with brain metastases treated with TDM1 after failure of next generation HER2 targeted therapies | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Prolonged survival in a HER2 positive metastatic breast cancer patient with brain metastases treated with TDM1 after failure of next generation HER2 targeted therapies Benedetta Trevisan, Deborah Cosentini, Greta Schivardi, Francesca Piazza, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6783648/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Brain metastases (BM) occur in up to 50% of patients with HER2-positive metastatic breast cancer (MBC) and represent a major clinical challenge due to limited CNS drug penetration. In recent years, novel anti-HER2 agents—such as trastuzumab deruxtecan (T-DXd) and tucatinib—have shown promising intracranial efficacy and are now recommended after progression on first-line therapies. However, no prospective data are available to guide optimal treatment sequencing, particularly in the CNS setting. Case Presentation: We report the case of a 37-year-old woman with HER2-positive, hormone receptor-negative MBC and symptomatic BM who progressed after treatment with T-DXd and a tucatinib-based regimen. Remarkably, fourth-line therapy with T-DM1 resulted in a durable intracranial response, maintained over 24 months, with good clinical tolerance and manageable side effects. Results: this case underscores the potential of T-DM1 to remain an effective treatment option even after the failure of next-generation HER2-targeted therapies. The sustained response may be attributed to tumor biology, prior radiotherapy-induced modulation of the blood–brain barrier, or enhanced drug delivery to CNS lesions. Given its favorable toxicity profile and ease of administration, T-DM1 retains clinical relevance in selected patients. Conclusion: T-DM1 may offer meaningful benefit in HER2+ MBC with BM, especially where newer agents fail or are contraindicated. Further studies are needed to clarify optimal sequencing strategies. Introduction Human epidermal growth factor receptor 2–positive breast cancer (HER2 + BC) accounts for approximately 15–20% of all BC cases and is associated with an aggressive clinical phenotype, characterized by a higher risk of recurrence and poorer prognosis 1 , 2 . Brain metastases (BM) are more frequently detected in HER2 + BC compared to other molecular subtypes. It is estimated that up to 25–50% of women with metastatic HER2 + BC will develop BM during the course of their disease 3 . Over the past decades, the introduction of anti-HER2 therapies, starting with trastuzumab, has significantly improved progression-free (PFS) and overall survival (OS) by achieving effective extracranial disease control. However, this benefit is less evident in patients with BM, who continue to experience high mortality rates due to the limited efficacy of systemic therapies in the central nervous system (CNS) 2 , 4 . Management of BM often includes local therapies like surgical resection, stereotactic radiosurgery, stereotactic radiotherapy, or whole-brain radiation therapy 5 . Recently, significant advances have been made in the systemic treatment of BMs with the introduction of novel agents, including antibody-drug conjugates (ADCs) such as trastuzumab deruxtecan (T-DXd) and targeted therapies like tucatinib, which have demonstrated promising efficacy and may be offered to patients with HER2-positive metastatic breast cancer (MBC) who have progressed on at least one prior HER2-directed therapy 6 . Several studies—including retrospective analyses, non-randomized trials, and exploratory analyses of randomized trials—have demonstrated the intracranial activity of T-DXd in patients with HER2 + MBC with BM. The TUXEDO 7 and DEBBRAH 8 trials reported intracranial response rates of 73.3% and 46.2%, respectively. The exploratory analyses from DESTINY trials 9 – 11 , have established the role of T-DXd as the treatment of choice in HER2 + MBC with BM even in heavily pretreated patients. In the 2024 pooled analysis of the DESTINY-Breast 01, 02, and 03 trials, trastuzumab deruxtecan (T-DXd) demonstrated superior CNS efficacy, with intracranial objective response rates (ORRs) of 45.2% in patients with treated/stable brain metastases and 45.5% in those with untreated/active lesions, compared to ORRs of 27.6% and 12% observed in the control arms receiving physician’s choice or T-DM1, respectively 12 . These findings were corroborated by the DESTINY-Breast 12 trial, specifically designed to assess CNS activity, which confirmed substantial intracranial response in both active and stable BM 13 . HER2-CLIMB study showed that the tucatinib-based combination provided a significant survival benefit in patients with HER + MBC, including those with active or stable brain metastases previously treated with trastuzumab, pertuzumab, and T-DM1 14–16 . Based on these results, T-DXd and tucatinib are recommended therapeutic options for patients with HER2 + MBC, according to both ASCO and ESMO clinical guidelines, following progression on first-line treatment with pertuzumab and trastuzumab even in the presence of BM 5 , 17 . Despite the increasing availability of anti-HER2 agents, prospective data guiding the optimal sequencing of these therapies remain lacking. As a result, therapeutic decision-making beyond the third line remains particularly challenging, especially in the setting of CNS progression. Here, we report the clinical case of a patient with HER2 + MBC and BM who experienced rapid disease progression on next-generation HER2-targeted therapies,yet achieved an unexpectedly durable clinical and radiological response with T-DM1—raising important questions about therapeutic sequencing and resistance mechanisms. Case presentation In March 2019, a 37-year-old black woman was diagnosed with HER2-positive, hormone receptor-negative locally advanced breast cancer. A core needle biopsy of a 6 cm retroareolar lesion in the left breast revealed an invasive carcinoma, and fine-needle aspiration cytology confirmed axillary lymph node involvement. According to immunohistochemical analysis, the tumor was negative for estrogen and progesterone receptors, exhibited a high proliferative activity with a Ki-67 index of 38%, and showed HER2 overexpression with an immunohistochemical score of 3+. Following multidisciplinary discussion, and considering the disease stage, tumor biology, and the patient’s excellent clinical condition (ECOG Performance Status 0), neoadjuvant systemic therapy with docetaxel, pertuzumab, and trastuzumab was started. The patient underwent a mastectomy with axillary lymph node dissection in October 2019 due to the favorable clinical response; histopathological examination revealed a complete pathological response in the breast (ypTis) and no residual axillary disease. Adjuvant therapy with trastuzumab and pertuzumab was continued for 14 additional administrations, completing the planned one-year treatment duration, and was discontinued in August 2020. Twelve months after discontinuation of anti-HER2 therapy, in August 2021, the patient reported a new-onset headache that was unresponsive to analgesics. Contrast-enhanced brain computed tomography (CT) and magnetic resonance imaging (MRI) revealed a single enhancing intra-axial lesion in the left posterior temporal lobe, associated with significant perilesional edema, while staging CT scan of the chest and abdomen showed no evidence of extracranial disease. Following multidisciplinary evaluation, the patient underwent surgical resection of the intracranial lesion, and histopathological analysis confirmed that the metastatic breast carcinoma was consistent with the molecular profile of the primary tumor. In September 2021, a follow-up brain MRI revealed disease recurrence at the surgical site, and the patient subsequently underwent stereotactic body radiotherapy (SBRT) with a dose of 24 Gy to the posterior temporal lesion. First-line systemic treatment with paclitaxel, trastuzumab, and pertuzumab was initiated; however, in December 2021, after only three months of treatment, MRI revealed disease progression with two new lesions: an 8 mm lesion in the temporo-occipital region and a 6 mm lesion herniating through the posterior craniotomy site. Due to the oligoprogressive nature and accessibility of the anatomical site, the patient was treated with cyberknife radiosurgery in February 2022 and continued with the same systemic therapy. By July 2022, new lesions were detected in the surgical cavity, left cerebellum, and left occipital lobe, accompanied by the onset of headache and visual disturbances. Given the prior radiation exposure, additional radiotherapy was not indicated, and in August 2022, the patient commenced second-line therapy with T-DXd. After three months of treatment, in November 2022, brain MRI demonstrated further disease progression, with an increase in both the size and number of metastases in the left superior cerebellar and occipital lobes. The confirmation of normal dihydropyrimidine dehydrogenase activity led to the introduction of third-line treatment with capecitabine, tucatinib, and trastuzumab, which resulted in a progression-free survival of four months. In March 2023, brain MRI revealed further progression in the left occipital and cerebellar regions, with cortico-meningeal enhancement in the left cerebellum leading to the initiation of fourth-line treatment with T-DM1. At the first radiological re-evaluation after four months of T-DM1 treatment, performed in July 2023, brain MRI demonstrated an initial intracranial response, with resolution of cortico-meningeal enhancement in the left cerebellum and a reduction in contrast enhancement in the left temporo-occipital region. The intracranial response has been maintained across all subsequent follow-up imaging assessments, including the most recent in March 2025. The patient remains on T-DM1 therapy with good clinical tolerance, 24 months after starting treatment. Discussion Despite the detrimental impact of CNS metastases on quality of life, therapeutic strategies for advanced or recurrent HER2-positive breast cancer are evolving rapidly, driven by the emergence of novel anti-HER2 agents, including ADCs and tyrosine kinase inhibitors. In particular, trastuzumab deruxtecan (T-DXd) and tucatinib-based regimens have shown unprecedented intracranial efficacy and are now widely recommended in updated clinical guidelines. However, the expanding landscape of HER2-targeted therapies has not been matched by prospective clinical trials addressing treatment sequencing, especially after the failure of next-generation agents. In the absence of robust sequencing data, clinicians are often left to make empiric decisions beyond the third line of therapy, particularly in patients with CNS involvement. Prior to the approval of T-DXd, T-DM1 was the standard second-line therapy based on the results of the EMILIA study 18–20 and it is now recommended when T-DXd is either unavailable or contraindicated, such as in patients with interstitial lung disease 17 . Although T-DM1 is currently considered a therapeutic option after newer anti-HER2 agents in clinical guidelines 5,17 , the sustained response observed in our patient highlights its continued relevance in selected cases and raises important questions about the mechanisms underlying this response. This observation also prompts a broader discussion on the potential benefits of introducing T-DM1 earlier in the treatment algorithm for selected patients with BM. Although its impact on PFS is limited, T-DM1 has demonstrated improved OS and clinical benefit in patients with BM from HER2+ MBC, as shown in EMILIA 18–20 , TH3RESA 21 , and KAMILLA 22 studies, with additional support from case reports and retrospective analyses highlighting neurological symptom improvements 23–26 . In this patient with HER2+ MBC and symptomatic brain metastases, T-DM1 achieved a sustained intracranial response lasting over 24 months, despite rapid disease progression on both T-DXd and a tucatinib-based combination. This exceptional response may be explained by individual tumor biology, radiotherapy-induced disruption of the blood–tumor barrier (BTB), or a potential synergistic effect that enhanced T-DM1 penetration and activity within the CNS. Several studies have demonstrated that T-DM1 is capable of penetrating the altered blood–tumor barrier (BTB), and emerging evidence suggests that prior radiotherapy may further enhance this permeability. 27,28 . In our patient, it is plausible that radiotherapy-induced disruption of the BTB favored enhanced T-DM1 delivery to the CNS, potentially amplifying its therapeutic effect and contributing to the sustained clinical and radiological response observed. Given that T-DXd and T-DM1 have similar sizes (10–15 nm) and were both administered after radiotherapy, we cannot suggest a greater penetration into the brain for T-DM1. However, we cannot rule out that the molecule administered later may have encountered a more compromised blood–brain barrier in this specific case 29,30. It cannot be excluded, although in the absence of strong and concrete supporting data, that interposing two ADCs with a drug having a different mechanism of action, such as a small molecule targeted therapy, may have enhanced the activity of T-DXd. Since the efficacy of second-generation ADCs, such as T-DM1, is strongly associated with target expression, it is possible that tucatinib treatment may have influenced HER2 receptor ri-expression, or that the drug’s efficacy could be partially mediated by HER2-independent mechanisms 31. This case underscores several key points: 1-T-DM1 may retain therapeutic efficacy even after failure of next-generation HER2-targeted agents; 2-prior radiotherapy may enhance ADC activity in the CNS by increasing BTB permeability; 3-in the absence of sequencing data, T-DM1 remains a viable and clinically valuable option beyond the third line, particularly in patients with good performance status and limited brain disease; 4-T-DM1 offers a favorable safety profile, ease of administration, and quality-of-life preservation, which are especially relevant in the context of CNS disease. In conclusion, this case strongly underscores the potential efficacy of T-DM1 in the treatment of HER2-positive MBC with BM, even after failure of next-generation HER2-targeted agents such as T-DXd and tucatinib. The patient achieved a remarkable and sustained intracranial response, maintained for over 24 months, with excellent clinical tolerance and preserved quality of life. This outcome is particularly significant given the rapid progression observed under more recent therapies, and it highlights the continued therapeutic value of T-DM1 in a clinical context where CNS-active options remain limited. Although currently positioned after newer agents in clinical guidelines, T-DM1 has demonstrated durable intracranial activity and could be considered in selected patients, particularly those with favourable clinical conditions, limited brain disease, or contraindications to next-generation therapies. Prior radiotherapy and specific tumor biology may have contributed to enhanced drug penetration across the blood–tumor barrier, further supporting its efficacy in the CNS. The lack of prospective data on treatment sequencing beyond the third line of therapy makes this case particularly relevant in clinical practice. This case challenges current sequencing paradigms and supports the reconsideration of T-DM1 as an active agent with durable CNS efficacy, highlighting the need for prospective studies in HER2+ MBC with brain metastases. Declarations Funding Declaration: this work didn’t received funding. Clinical trial number: not applicable Ethics approval: Informed consent was obtained from the patient before starting the treatment accordigly with the local Ethical commettee ASST-Spedali Civili di Brescia. Patient was treated in compliance with Good Clinical Practice standards and the ethical principles outlined in the Declaration of Helsinki. Consent to Publish declaration: The patient consented to the publication of the images and clinical information presented. Consent to Participate declaration: not applicable Author Contribution B.T., D.C., G.S., F.P., G.S., L.M., L.V., G.I., F.D., A.B., M.L., and R.P. wrote the first draft of the manuscript and contributed to the critical revision.D.C., G.S., F.P., and G.S. .revised the main draft and contributed to the discussion.M.L. and R.P. supervised the project and provided overall direction.All authors read and approved the final version of the manuscript. References Huszno, J. & Nowara, E. Risk factors for disease progression in HER2-positive breast cancer patients based on the location of metastases. Przeglad Menopauzalny (2015) doi:10.5114/pm.2015.54341. Müller, V. et al. Epidemiology, clinical outcomes, and unmet needs of patients with human epidermal growth factor receptor 2-positive breast cancer and brain metastases: A systematic literature review. Cancer Treatment Reviews Preprint at https://doi.org/10.1016/j.ctrv.2023.102527 (2023). Tomasik, B. et al. 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Trastuzumab emtansine versus treatment of physician’s choice in patients with previously treated HER2-positive metastatic breast cancer (TH3RESA): final overall survival results from a randomised open-label phase 3 trial. Lancet Oncol (2017) doi:10.1016/S1470-2045(17)30313-3. Montemurro, F. et al. Safety of trastuzumab emtansine (T-DM1) in patients with HER2-positive advanced breast cancer: Primary results from the KAMILLA study cohort 1. Eur J Cancer 109 , 92–102 (2019). Ricciardi, G. R. R. et al. Efficacy of T-DM1 for leptomeningeal and brain metastases in a HER2 positive metastatic breast cancer patient: New directions for systemic therapy - a case report and literature review. BMC Cancer (2018) doi:10.1186/s12885-018-3994-5. Kalsi, R. et al. Brain metastasis and response to ado-trastuzumab emtansine: A case report and literature review. Clin Breast Cancer (2015) doi:10.1016/j.clbc.2014.10.003. Jacot, W. et al. Efficacy and safety of trastuzumab emtansine (T-DM1) in patients with HER2-positive breast cancer with brain metastases. Breast Cancer Res Treat (2016) doi:10.1007/s10549-016-3828-6. Fabi, A. et al. T-DM1 and brain metastases: Clinical outcome in HER2-positive metastatic breast cancer. Breast (2018) doi:10.1016/j.breast.2018.07.004. Teng, F., Tsien, C. I., Lawrence, T. S. & Cao, Y. Blood–tumor barrier opening changes in brain metastases from pre to one-month post radiation therapy. Radiotherapy and Oncology (2017) doi:10.1016/j.radonc.2017.08.006. Cao, Y. et al. Use of magnetic resonance imaging to assess blood-brain/blood-glioma barrier opening during conformal radiotherapy. Journal of Clinical Oncology (2005) doi:10.1200/JCO.2005.07.144. Center for drug evaluation and research application number: 125427orig1s000 clinical pharmacology and biopharmaceutics review(s) . Joubert, N., Beck, A., Dumontet, C. & Denevault-Sabourin, C. Antibody–drug conjugates: The last decade. Pharmaceuticals vol. 13 1–30 Preprint at https://doi.org/10.3390/ph13090245 (2020). Baselga, J. et al. Relationship between tumor biomarkers and efficacy in EMILIA, a phase III study of trastuzumab emtansine in HER2-Positive metastatic breast cancer. Clinical Cancer Research 22 , 3755–3763 (2016). Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6783648","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":486369901,"identity":"2b302eb7-f21c-4661-9266-5018ba5ef619","order_by":0,"name":"Benedetta Trevisan","email":"","orcid":"","institution":"University of Brescia, ASST Spedali Civili","correspondingAuthor":false,"prefix":"","firstName":"Benedetta","middleName":"","lastName":"Trevisan","suffix":""},{"id":486369902,"identity":"119d40fd-9648-47ca-8fcc-4efbadeeb0b8","order_by":1,"name":"Deborah Cosentini","email":"","orcid":"","institution":"University of Brescia, ASST Spedali 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10:08:28","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6783648/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6783648/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":87887228,"identity":"d8f37d30-2dfe-429f-8182-1044d9ae5473","added_by":"auto","created_at":"2025-07-30 05:35:13","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":477849,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6783648/v1/39a2bbc9-9d02-4e4b-899a-353d02013b86.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Prolonged survival in a HER2 positive metastatic breast cancer patient with brain metastases treated with TDM1 after failure of next generation HER2 targeted therapies","fulltext":[{"header":"Introduction","content":"\u003cp\u003eHuman epidermal growth factor receptor 2\u0026ndash;positive breast cancer (HER2\u0026thinsp;+\u0026thinsp;BC) accounts for approximately 15\u0026ndash;20% of all BC cases and is associated with an aggressive clinical phenotype, characterized by a higher risk of recurrence and poorer prognosis \u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. Brain metastases (BM) are more frequently detected in HER2\u0026thinsp;+\u0026thinsp;BC compared to other molecular subtypes. It is estimated that up to 25\u0026ndash;50% of women with metastatic HER2\u0026thinsp;+\u0026thinsp;BC will develop BM during the course of their disease \u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. Over the past decades, the introduction of anti-HER2 therapies, starting with trastuzumab, has significantly improved progression-free (PFS) and overall survival (OS) by achieving effective extracranial disease control. However, this benefit is less evident in patients with BM, who continue to experience high mortality rates due to the limited efficacy of systemic therapies in the central nervous system (CNS)\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. Management of BM often includes local therapies like surgical resection, stereotactic radiosurgery, stereotactic radiotherapy, or whole-brain radiation therapy \u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eRecently, significant advances have been made in the systemic treatment of BMs with the introduction of novel agents, including antibody-drug conjugates (ADCs) such as trastuzumab deruxtecan (T-DXd) and targeted therapies like tucatinib, which have demonstrated promising efficacy and may be offered to patients with HER2-positive metastatic breast cancer (MBC) who have progressed on at least one prior HER2-directed therapy \u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. Several studies\u0026mdash;including retrospective analyses, non-randomized trials, and exploratory analyses of randomized trials\u0026mdash;have demonstrated the intracranial activity of T-DXd in patients with HER2\u0026thinsp;+\u0026thinsp;MBC with BM. The TUXEDO\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e and DEBBRAH\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e trials reported intracranial response rates of 73.3% and 46.2%, respectively. The exploratory analyses from DESTINY trials \u003csup\u003e\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e, have established the role of T-DXd as the treatment of choice in HER2\u0026thinsp;+\u0026thinsp;MBC with BM even in heavily pretreated patients. In the 2024 pooled analysis of the DESTINY-Breast 01, 02, and 03 trials, trastuzumab deruxtecan (T-DXd) demonstrated superior CNS efficacy, with intracranial objective response rates (ORRs) of 45.2% in patients with treated/stable brain metastases and 45.5% in those with untreated/active lesions, compared to ORRs of 27.6% and 12% observed in the control arms receiving physician\u0026rsquo;s choice or T-DM1, respectively \u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. These findings were corroborated by the DESTINY-Breast 12 trial, specifically designed to assess CNS activity, which confirmed substantial intracranial response in both active and stable BM\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. HER2-CLIMB study showed that the tucatinib-based combination provided a significant survival benefit in patients with HER\u0026thinsp;+\u0026thinsp;MBC, including those with active or stable brain metastases previously treated with trastuzumab, pertuzumab, and T-DM1\u003csup\u003e14\u0026ndash;16\u003c/sup\u003e. Based on these results, T-DXd and tucatinib are recommended therapeutic options for patients with HER2\u0026thinsp;+\u0026thinsp;MBC, according to both ASCO and ESMO clinical guidelines, following progression on first-line treatment with pertuzumab and trastuzumab even in the presence of BM \u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eDespite the increasing availability of anti-HER2 agents, prospective data guiding the optimal sequencing of these therapies remain lacking. As a result, therapeutic decision-making beyond the third line remains particularly challenging, especially in the setting of CNS progression.\u003c/p\u003e\u003cp\u003eHere, we report the clinical case of a patient with HER2\u0026thinsp;+\u0026thinsp;MBC and BM who experienced rapid disease progression on next-generation HER2-targeted therapies,yet achieved an unexpectedly durable clinical and radiological response with T-DM1\u0026mdash;raising important questions about therapeutic sequencing and resistance mechanisms.\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cp\u003eIn March 2019, a 37-year-old black woman was diagnosed with HER2-positive, hormone receptor-negative locally advanced breast cancer. A core needle biopsy of a 6 cm retroareolar lesion in the left breast revealed an invasive carcinoma, and fine-needle aspiration cytology confirmed axillary lymph node involvement. According to immunohistochemical analysis, the tumor was negative for estrogen and progesterone receptors, exhibited a high proliferative activity with a Ki-67 index of 38%, and showed HER2 overexpression with an immunohistochemical score of 3+. Following multidisciplinary discussion, and considering the disease stage, tumor biology, and the patient\u0026rsquo;s excellent clinical condition (ECOG Performance Status 0), neoadjuvant systemic therapy with docetaxel, pertuzumab, and trastuzumab was started. The patient underwent a mastectomy with axillary lymph node dissection in October 2019 due to the favorable clinical response; histopathological examination revealed a complete pathological response in the breast (ypTis) and no residual axillary disease. Adjuvant therapy with trastuzumab and pertuzumab was continued for 14 additional administrations, completing the planned one-year treatment duration, and was discontinued in August 2020. Twelve months after discontinuation of anti-HER2 therapy, in August 2021, the patient reported a new-onset headache that was unresponsive to analgesics. Contrast-enhanced brain computed tomography (CT) and magnetic resonance imaging (MRI) revealed a single enhancing intra-axial lesion in the left posterior temporal lobe, associated with significant perilesional edema, while staging CT scan of the chest and abdomen showed no evidence of extracranial disease. Following multidisciplinary evaluation, the patient underwent surgical resection of the intracranial lesion, and histopathological analysis confirmed that the metastatic breast carcinoma was consistent with the molecular profile of the primary tumor. In September 2021, a follow-up brain MRI revealed disease recurrence at the surgical site, and the patient subsequently underwent stereotactic body radiotherapy (SBRT) with a dose of 24 Gy to the posterior temporal lesion. First-line systemic treatment with paclitaxel, trastuzumab, and pertuzumab was initiated; however, in December 2021, after only three months of treatment, MRI revealed disease progression with two new lesions: an 8 mm lesion in the temporo-occipital region and a 6 mm lesion herniating through the posterior craniotomy site. Due to the oligoprogressive nature and accessibility of the anatomical site, the patient was treated with cyberknife radiosurgery in February 2022 and continued with the same systemic therapy. By July 2022, new lesions were detected in the surgical cavity, left cerebellum, and left occipital lobe, accompanied by the onset of headache and visual disturbances. Given the prior radiation exposure, additional radiotherapy was not indicated, and in August 2022, the patient commenced second-line therapy with T-DXd. After three months of treatment, in November 2022, brain MRI demonstrated further disease progression, with an increase in both the size and number of metastases in the left superior cerebellar and occipital lobes. The confirmation of normal dihydropyrimidine dehydrogenase activity led to the introduction of third-line treatment with capecitabine, tucatinib, and trastuzumab, which resulted in a progression-free survival of four months. In March 2023, brain MRI revealed further progression in the left occipital and cerebellar regions, with cortico-meningeal enhancement in the left cerebellum leading to the initiation of fourth-line treatment with T-DM1. At the first radiological re-evaluation after four months of T-DM1 treatment, performed in July 2023, brain MRI demonstrated an initial intracranial response, with resolution of cortico-meningeal enhancement in the left cerebellum and a reduction in contrast enhancement in the left temporo-occipital region. The intracranial response has been maintained across all subsequent follow-up imaging assessments, including the most recent in March 2025. The patient remains on T-DM1 therapy with good clinical tolerance, 24 months after starting treatment.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eDespite the detrimental impact of CNS metastases on quality of life, therapeutic strategies for advanced or recurrent HER2-positive breast cancer are evolving rapidly, driven by the emergence of novel anti-HER2 agents, including ADCs and tyrosine kinase inhibitors. In particular, trastuzumab deruxtecan (T-DXd) and tucatinib-based regimens have shown unprecedented intracranial efficacy and are now widely recommended in updated clinical guidelines. However, the expanding landscape of HER2-targeted therapies has not been matched by prospective clinical trials addressing treatment sequencing, especially after the failure of next-generation agents. In the absence of robust sequencing data, clinicians are often left to make empiric decisions beyond the third line of therapy, particularly in patients with CNS involvement.\u003c/p\u003e\n\u003cp\u003ePrior to the approval of T-DXd, T-DM1 was the standard second-line therapy based on the results of the EMILIA study\u003csup\u003e\u0026nbsp;18–20\u003c/sup\u003e and it is now recommended when T-DXd is either unavailable or contraindicated, such as in patients with interstitial lung disease \u003csup\u003e17\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eAlthough T-DM1 is currently considered a therapeutic option after newer anti-HER2 agents in clinical guidelines \u003csup\u003e5,17\u003c/sup\u003e, the sustained response observed in our patient highlights its continued relevance in selected cases and raises important questions about the mechanisms underlying this response. This observation also prompts a broader discussion on the potential benefits of introducing T-DM1 earlier in the treatment algorithm for selected patients with BM. Although its impact on PFS is limited, T-DM1 has demonstrated improved OS and clinical benefit in patients with BM from HER2+ MBC, as shown in EMILIA \u003csup\u003e18–20\u003c/sup\u003e, TH3RESA\u0026nbsp;\u003csup\u003e21\u003c/sup\u003e, and KAMILLA\u0026nbsp;\u003csup\u003e22\u003c/sup\u003e studies, with additional support from case reports and retrospective analyses highlighting neurological symptom improvements \u003csup\u003e23–26\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eIn this patient with HER2+ MBC and symptomatic brain metastases, T-DM1 achieved a sustained intracranial response lasting over 24 months, despite rapid disease progression on both T-DXd and a tucatinib-based combination.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;This exceptional response may be explained by individual tumor biology, radiotherapy-induced disruption of the blood–tumor barrier (BTB), or a potential synergistic effect that enhanced T-DM1 penetration and activity within the CNS. \u0026nbsp;Several studies have demonstrated that T-DM1 is capable of penetrating the altered blood–tumor barrier (BTB), and emerging evidence suggests that prior radiotherapy may further enhance this permeability. \u003csup\u003e27,28\u003c/sup\u003e. In our patient, it is plausible that radiotherapy-induced disruption of the BTB favored enhanced T-DM1 delivery to the CNS, potentially amplifying its therapeutic effect and contributing to the sustained clinical and radiological response observed. Given that T-DXd and T-DM1 have similar sizes (10–15 nm) and were both administered after radiotherapy, we cannot suggest a greater penetration into the brain for T-DM1. However, we cannot rule out that the molecule administered later may have encountered a more compromised blood–brain barrier in this specific case\u003csup\u003e\u0026nbsp;29,30.\u003c/sup\u003e It cannot be excluded, although in the absence of strong and concrete supporting data, that interposing two ADCs with a drug having a different mechanism of action, such as a small molecule targeted therapy, may have enhanced the activity of T-DXd. Since the efficacy of second-generation ADCs, such as T-DM1, is strongly associated with target expression, it is possible that tucatinib treatment may have influenced HER2 receptor ri-expression, or that the drug’s efficacy could be partially mediated by HER2-independent mechanisms\u003csup\u003e\u0026nbsp;31.\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eThis case underscores several key points: 1-T-DM1 may retain therapeutic efficacy even after failure of next-generation HER2-targeted agents; 2-prior radiotherapy may enhance ADC activity in the CNS by increasing BTB permeability; 3-in the absence of sequencing data, T-DM1 remains a viable and clinically valuable option beyond the third line, particularly in patients with good performance status and limited brain disease; 4-T-DM1 offers a favorable safety profile, ease of administration, and quality-of-life preservation, which are especially relevant in the context of CNS disease.\u003c/p\u003e\n\u003cp\u003eIn conclusion, this case strongly underscores the potential efficacy of T-DM1 in the treatment of HER2-positive MBC with BM, even after failure of next-generation HER2-targeted agents such as T-DXd and tucatinib. The patient achieved a remarkable and sustained intracranial response, maintained for over 24 months, with excellent clinical tolerance and preserved quality of life. This outcome is particularly significant given the rapid progression observed under more recent therapies, and it highlights the continued therapeutic value of T-DM1 in a clinical context where CNS-active options remain limited. Although currently positioned after newer agents in clinical guidelines, T-DM1 has demonstrated durable intracranial activity and could be considered in selected patients, particularly those with favourable clinical conditions, limited brain disease, or contraindications to next-generation therapies. Prior radiotherapy and specific tumor biology may have contributed to enhanced drug penetration across the blood–tumor barrier, further supporting its efficacy in the CNS.\u003c/p\u003e\n\u003cp\u003eThe lack of prospective data on treatment sequencing beyond the third line of therapy makes this case particularly relevant in clinical practice. This case challenges current sequencing paradigms and supports the reconsideration of T-DM1 as an active agent with durable CNS efficacy, highlighting the need for prospective studies in HER2+ MBC with brain metastases.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding Declaration:\u0026nbsp;\u003c/strong\u003e this work didn’t received funding.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial number:\u0026nbsp;\u003c/strong\u003enot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval:\u0026nbsp;\u003c/strong\u003eInformed consent was obtained from the patient before starting the treatment accordigly with the local Ethical commettee ASST-Spedali Civili di Brescia. Patient was treated in compliance with Good Clinical Practice standards and the ethical principles outlined in the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to Publish declaration:\u003c/strong\u003e The patient consented to the publication of the images and clinical information presented.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to Participate declaration:\u003c/strong\u003e not applicable\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eB.T., D.C., G.S., F.P., G.S., L.M., L.V., G.I., F.D., A.B., M.L., and R.P. wrote the first draft of the manuscript and contributed to the critical revision.D.C., G.S., F.P., and G.S. .revised the main draft and contributed to the discussion.M.L. and R.P. supervised the project and provided overall direction.All authors read and approved the final version of the manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eHuszno, J. \u0026amp; Nowara, E. Risk factors for disease progression in HER2-positive breast cancer patients based on the location of metastases. \u003cem\u003ePrzeglad Menopauzalny\u003c/em\u003e (2015) doi:10.5114/pm.2015.54341.\u003c/li\u003e\n\u003cli\u003eM\u0026uuml;ller, V. \u003cem\u003eet al.\u003c/em\u003e Epidemiology, clinical outcomes, and unmet needs of patients with human epidermal growth factor receptor 2-positive breast cancer and brain metastases: A systematic literature review. \u003cem\u003eCancer Treatment Reviews\u003c/em\u003e Preprint at https://doi.org/10.1016/j.ctrv.2023.102527 (2023).\u003c/li\u003e\n\u003cli\u003eTomasik, B. \u003cem\u003eet al.\u003c/em\u003e Molecular aspects of brain metastases in breast cancer. \u003cem\u003eCancer Treatment Reviews\u003c/em\u003e Preprint at https://doi.org/10.1016/j.ctrv.2023.102521 (2023).\u003c/li\u003e\n\u003cli\u003eLindegger, N. \u003cem\u003eet al.\u003c/em\u003e 308P Real-world outcomes among HER2+ metastatic breast cancer patients with brain metastases. \u003cem\u003eAnnals of Oncology\u003c/em\u003e (2020) doi:10.1016/j.annonc.2020.08.410.\u003c/li\u003e\n\u003cli\u003eRamakrishna, N., Anders, C. 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E. \u003cem\u003eet al.\u003c/em\u003e Trastuzumab emtansine versus treatment of physician\u0026rsquo;s choice in patients with previously treated HER2-positive metastatic breast cancer (TH3RESA): final overall survival results from a randomised open-label phase 3 trial. \u003cem\u003eLancet Oncol\u003c/em\u003e (2017) doi:10.1016/S1470-2045(17)30313-3.\u003c/li\u003e\n\u003cli\u003eMontemurro, F. \u003cem\u003eet al.\u003c/em\u003e Safety of trastuzumab emtansine (T-DM1) in patients with HER2-positive advanced breast cancer: Primary results from the KAMILLA study cohort 1. \u003cem\u003eEur J Cancer\u003c/em\u003e \u003cstrong\u003e109\u003c/strong\u003e, 92\u0026ndash;102 (2019).\u003c/li\u003e\n\u003cli\u003eRicciardi, G. R. R. \u003cem\u003eet al.\u003c/em\u003e Efficacy of T-DM1 for leptomeningeal and brain metastases in a HER2 positive metastatic breast cancer patient: New directions for systemic therapy - a case report and literature review. \u003cem\u003eBMC Cancer\u003c/em\u003e (2018) doi:10.1186/s12885-018-3994-5.\u003c/li\u003e\n\u003cli\u003eKalsi, R. \u003cem\u003eet al.\u003c/em\u003e Brain metastasis and response to ado-trastuzumab emtansine: A case report and literature review. \u003cem\u003eClin Breast Cancer\u003c/em\u003e (2015) doi:10.1016/j.clbc.2014.10.003.\u003c/li\u003e\n\u003cli\u003eJacot, W. \u003cem\u003eet al.\u003c/em\u003e Efficacy and safety of trastuzumab emtansine (T-DM1) in patients with HER2-positive breast cancer with brain metastases. \u003cem\u003eBreast Cancer Res Treat\u003c/em\u003e (2016) doi:10.1007/s10549-016-3828-6.\u003c/li\u003e\n\u003cli\u003eFabi, A. \u003cem\u003eet al.\u003c/em\u003e T-DM1 and brain metastases: Clinical outcome in HER2-positive metastatic breast cancer. \u003cem\u003eBreast\u003c/em\u003e (2018) doi:10.1016/j.breast.2018.07.004.\u003c/li\u003e\n\u003cli\u003eTeng, F., Tsien, C. I., Lawrence, T. S. \u0026amp; Cao, Y. Blood\u0026ndash;tumor barrier opening changes in brain metastases from pre to one-month post radiation therapy. \u003cem\u003eRadiotherapy and Oncology\u003c/em\u003e (2017) doi:10.1016/j.radonc.2017.08.006.\u003c/li\u003e\n\u003cli\u003eCao, Y. \u003cem\u003eet al.\u003c/em\u003e Use of magnetic resonance imaging to assess blood-brain/blood-glioma barrier opening during conformal radiotherapy. \u003cem\u003eJournal of Clinical Oncology\u003c/em\u003e (2005) doi:10.1200/JCO.2005.07.144.\u003c/li\u003e\n\u003cli\u003e\u003cem\u003eCenter for drug evaluation and research application number: 125427orig1s000 clinical pharmacology and biopharmaceutics review(s)\u003c/em\u003e.\u003c/li\u003e\n\u003cli\u003eJoubert, N., Beck, A., Dumontet, C. \u0026amp; Denevault-Sabourin, C. Antibody\u0026ndash;drug conjugates: The last decade. \u003cem\u003ePharmaceuticals\u003c/em\u003e vol. 13 1\u0026ndash;30 Preprint at https://doi.org/10.3390/ph13090245 (2020).\u003c/li\u003e\n\u003cli\u003eBaselga, J. \u003cem\u003eet al.\u003c/em\u003e Relationship between tumor biomarkers and efficacy in EMILIA, a phase III study of trastuzumab emtansine in HER2-Positive metastatic breast cancer. \u003cem\u003eClinical Cancer Research\u003c/em\u003e \u003cstrong\u003e22\u003c/strong\u003e, 3755\u0026ndash;3763 (2016).\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-6783648/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6783648/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Brain metastases (BM) occur in up to 50% of patients with HER2-positive metastatic breast cancer (MBC) and represent a major clinical challenge due to limited CNS drug penetration. In recent years, novel anti-HER2 agents—such as trastuzumab deruxtecan (T-DXd) and tucatinib—have shown promising intracranial efficacy and are now recommended after progression on first-line therapies. However, no prospective data are available to guide optimal treatment sequencing, particularly in the CNS setting.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase Presentation:\u003c/strong\u003e We report the case of a 37-year-old woman with HER2-positive, hormone receptor-negative MBC and symptomatic BM who progressed after treatment with T-DXd and a tucatinib-based regimen. Remarkably, fourth-line therapy with T-DM1 resulted in a durable intracranial response, maintained over 24 months, with good clinical tolerance and manageable side effects.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e this case underscores the potential of T-DM1 to remain an effective treatment option even after the failure of next-generation HER2-targeted therapies. The sustained response may be attributed to tumor biology, prior radiotherapy-induced modulation of the blood–brain barrier, or enhanced drug delivery to CNS lesions. Given its favorable toxicity profile and ease of administration, T-DM1 retains clinical relevance in selected patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e T-DM1 may offer meaningful benefit in HER2+ MBC with BM, especially where newer agents fail or are contraindicated. Further studies are needed to clarify optimal sequencing strategies.\u003c/p\u003e","manuscriptTitle":"Prolonged survival in a HER2 positive metastatic breast cancer patient with brain metastases treated with TDM1 after failure of next generation HER2 targeted therapies","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-17 16:24:16","doi":"10.21203/rs.3.rs-6783648/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"23663d2e-c3b1-40b7-8c83-ce3ff9fb7ef3","owner":[],"postedDate":"July 17th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-07-30T05:27:02+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-17 16:24:16","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6783648","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6783648","identity":"rs-6783648","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}