Complete Remission and Radical Resection of Metastatic Inflammatory Breast Cancer Using Bevacizumab, Paclitaxel, and Fulvestrant

Complete Remission and Radical Resection of Metastatic Inflammatory Breast Cancer Using Bevacizumab, Paclitaxel, and Fulvestrant | 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 Complete Remission and Radical Resection of Metastatic Inflammatory Breast Cancer Using Bevacizumab, Paclitaxel, and Fulvestrant Masahiro Kishimoto, Chisa Murazawa, Ayako Sugihara This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6157011/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 In most cases, unresectable metastatic breast cancer (MBC) is incurable. We report a case of bilateral inflammatory breast cancer with multiple pulmonary and distant lymph node metastatic lesions, achieving complete remission of distant metastases and curative resection of the primary lesions through combined regimen of bevacizumab, paclitaxel, and fulvestrant. A 65-year-old female patient presented with hormone receptor-positive, HER2-negative breast cancer with extensive inflammatory changes in the bilateral breast and skin, accompanied by multiple pulmonary and distant lymph node metastatic lesions. Treatment with bevacizumab, paclitaxel, and fulvestrant, resulted in complete remission of distant metastases and primary lesion reduction, enabling curative resection. At 54 months from treatment initiation and 42 months post-surgery, the patient remained disease-free. Based on this case, the combined use of bevacizumab, paclitaxel, and fulvestrant might eradicate distant metastases and facilitate curative resection in unresectable primary tumors. This treatment should be considered in patients with inoperable MBC. Figures Figure 1 Figure 2 Figure 3 Introduction Metastatic breast cancer (MBC) has traditionally been considered incurable, with treatment goals focused on palliation and prolongation of survival 1 , 2 . The median overall survival (OS) of patients with hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer is 44.8 months 3 . Inflammatory breast cancer is an aggressive type of breast cancer characterized by rapid progression and poor prognosis 4 . The survival rates of patients with metastatic inflammatory breast cancer are poor, with a median OS of 26.0–28.4 months 5 , 6 , 7 . The combined use of paclitaxel, a taxane-based anticancer drug, and bevacizumab, a humanized monoclonal antibody that targets all isoforms of vascular endothelial growth factor (VEGF)-A, is associated with a better progression-free survival (PFS) compared with paclitaxel alone. However, such treatment did not improve OS 8 , and the complete response (CR) rate was low at 4%. Fulvestrant, a selective estrogen receptor degrading agent, improves PFS compared to anastrozole, an aromatase inhibitor. Although the CR rate for both fulvestrant and anastrozole was 3%, fulvestrant did not improve the CR rate. 9 . The combination of endocrine therapy and bevacizumab was well tolerated and associated with a superior PFS compared with endocrine therapy alone 10 . However, the CR rate was low at 5% 11 . In vitro and in vivo studies have reported the combined effects of fulvestrant and chemotherapeutic agents, particularly docetaxel, a taxane-based anticancer drug 12 . However, there are no reports about its clinical combination effects. Herein, we present a case in which the combination of bevacizumab, paclitaxel, and fulvestrant resulted in the disappearance of all distant metastatic lesions, thereby enabling the radical resection of bilateral inflammatory breast cancer and achieving a long-term disease-free status. Results Case history and presentation In June 2020, a 65-year-old female patient presented with extensive erythema extending from both breasts to the upper abdomen (Fig. 1 a). Pathological evaluation revealed invasive ductal carcinoma of the bilateral breasts (pT4d, Ki-67 index of 50%) with dermal lymphatic invasion, which is consistent with inflammatory breast cancer. The tumors were estrogen receptor-positive (100%), progesterone receptor-positive (80%) and HER2-negative (1+). Contrast-enhanced computed tomography (CT) scan revealed over 8,000 pulmonary, cervical, mediastinal (Figs. 2 a, b and c), supraclavicular, infraclavicular, and axillary lymph node metastatic lesions. The patient had a history of type 2 diabetes and hypertension, with baseline blood glucose level at 256 mg/dL, hemoglobin A1C level at 8.1% and triglyceride level at 172 mg/dL. Her body mass index was 30 kg/m 2 . Urinalysis showed glycosuria (+ 4), proteinuria (±) and hematuria (+ 2). Management Systemic therapy was initiated with bevacizumab (10 mg/kg intravenously on days 1 and 15 every 4 weeks) and paclitaxel (80 mg/m² intravenously on days 1, 8, and 15 every 4 weeks), combined with fulvestrant (500 mg intramuscularly on days 1, 15, and 29, then every 28 days). After 1 month, the treatment was interrupted as the patient had mild interstitial pneumonia caused by the coronavirus disease 2019. However, it was resumed after the patient recovered without significant residual symptoms. At 11 months post-treatment initiation, a CT scan revealed a significant reduction or disappearance of all pulmonary and lymph node metastatic lesions. The level of the tumor marker breast cancer antigen 225 continuously declined from baseline levels up to the time of surgery. Meanwhile, the cancer antigen 15 − 3 levels initially increased after treatment initiation but subsequently decreased significantly before surgery (Fig. 3 ). Adverse events and treatment adjustments The hematologic adverse events included grade 2 leukopenia, neutropenia, lymphopenia, and anemia. Further, grade 1 elevations in aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyl transpeptidase levels were observed. The paclitaxel dosing was reduced by 15% on one occasion. As proteinuria progressed to 3+, bevacizumab and paclitaxel were discontinued. The patient was later treated with eribulin (1.4 mg/m² intravenously on days 1 and 8 every 3 weeks) at a reduced dose (from 39–13% of the full dose) for two cycles. Thereafter, proteinuria improved to ± within 3 weeks of treatment discontinuation. Radiation therapy The combination of bevacizumab, paclitaxel, and fulvestrant resulted in the improvement of inflammatory breast cancer in both sides of the chest. However, erythema persisted. Therefore, during eribulin treatment, radiation therapy was administered to both chest walls at 2 Gy per fraction for a total of 25 fractions, with a total dose of 50 Gy. Nevertheless, the erythema did not completely resolve (Fig. 1 b). Surgical intervention Despite the reduction in erythema, residual skin changes persisted, requiring bilateral mastectomy, extensive skin excision, and lymph node dissection at 12 months post-treatment initiation. The skin excision margins were histologically evaluated in 2-cm sections (with a total of 52 specimens). Residual cancer was found in 33 sections, and additional excision was performed until all the margins were cancer-free (Fig. 1 c). The wound was then closed using a rectus abdominis skin flap. Skin engraftment was good except in a small area on the upper left lateral side. After 1 month, the skin was harvested from the left thigh and grafted to the left upper lateral side, and the remaining area also had good skin grafting. The excised specimen contained diffuse residual invasive ductal carcinoma extending from the subcutaneous tissue to the dermis (longest diameter: 48 cm). Tumor cell infiltration was observed in the axillary fat tissue bilaterally. However, the lymph nodes presented with coagulative necrosis without viable tumor cells. Notably, the residual tumor transformed into a triple-negative phenotype (ER−, PgR−, HER2 − and Ki-67 of 1%). The primary tumor, which had ultimately metastasized to both sides of the chest, was completely resected. Long-term outcomes Fulvestrant therapy was resumed on postoperative day 15, followed by oral doxifluridine (800 mg/day), a prodrug of 5-fluorouracil, and cyclophosphamide (50 mg/day), an alkylating agent, on postoperative day 23. At 54 months post-treatment initiation, a CT scan confirmed sustained complete remission of distant metastases (Fig. 2 d, e, and f). There was no local recurrence 54 months after the start of treatment and 42 months after surgery (Fig. 1 d). Following surgery, the blood concentration of the tumor marker cancer antigen 15 − 3 continued to decline, and breast cancer antigen 225, which initially increased after treatment initiation, also showed a sustained decrease. This trend persisted, with both markers remaining at low levels up to the present day (42 months post-surgery), consistent with the patient’s ongoing disease-free status (Fig. 3 ). Discussion This study found two important clinical issues. The combination of bevacizumab, paclitaxel, and fulvestrant achieved complete remission of pulmonary and distant lymph node metastases in hormone receptor-positive, HER2-negative breast cancer. Even in the case of metastatic bilateral inflammatory breast cancer, long-term disease-free survival was achieved using the combination of these drugs, followed by curative resection of the primary tumor after complete remission of distant metastases and shrinkage of the primary lesion. First, the combination of bevacizumab, paclitaxel, and fulvestrant achieved complete remission of pulmonary and distant lymph node metastases. Compared with paclitaxel alone, the combination of paclitaxel and bevacizumab significantly prolonged PFS and increased the objective response rate. However, it did not improve OS 8 . In a preclinical study using a human xenograft model of non–small-cell lung cancer, estrogen induced resistance to bevacizumab 13 . However, blockade of the estrogen receptor pathway with fulvestrant can restore treatment sensitivity to bevacizumab in cases of estrogen induced resistance to bevacizumab, regardless of breast cancer type. In another preclinical study using breast cancer cell lines, VEGF stimulated the growth of VEGF receptor 2-positive tumor cells and overrides the growth-suppressive effects of anti-hormones via the expression and activity of Bcl-2 14 . Based on an analysis of the VEGF gene expression in human breast cancer, it was overexpressed in all 18 cancer tissues assessed compared with adjacent non-tumor tissues 15 . High VEGF levels in breast tumor tissues are associated with decreased response to anti-estrogen therapy in metastatic conditions 11 . Based on these results, the combination of bevacizumab and fulvestrant can enhance the therapeutic effect of the drugs. In phase II clinical trials, the combination of bevacizumab and fulvestrant was well tolerated, and the toxicity profile was consistent with the known toxicity profile of each single agent 11 , 16 . In a phase III clinical trial, the use of combined bevacizumab and endocrine as the first-line treatment did not significantly increase PFS or OS in women with advanced-stage breast cancer 17 . However, in a pooled analysis, the addition of bevacizumab to endocrine therapy increased the overall PFS, but not OS 10 . In a preclinical study, combination treatment with fulvestrant and taxanes in vitro exhibited synergistic effects in estrogen receptor-positive breast cancer cell lines 18 , 12 . In vivo, a combination of fulvestrant and docetaxel had a synergistic effect on tumor growth 12 . The synergistic effect of these drug combinations can be attributed to the downregulation of the chemoresistance factors Bcl2 and the microtubule-associated protein tau caused by fulvestrant. There are no clinical trials on the combination therapy of bevacizumab, paclitaxel, and fulvestrant. To the best of our knowledge, this case provides the first clinical evidence supporting the combined use of these drugs. Second, even in the case of metastatic bilateral inflammatory breast cancer, long-term disease-free survival was achieved using the combination of these drugs, followed by curative resection of the primary tumor after complete remission of distant metastases and shrinkage of the primary lesion. There are several clinical trials on the resection of the primary site for stage IV breast cancer. Previous studies on the resection of the primary site before systemic treatment have different results, particularly in terms of extending OS 19 , 20 . However, the OS did not improve with the resection of the primary site after systemic treatment when distant metastases persist 21 . However, to date, there are no clinical trials examining the resection of the primary site after the disappearance of distant metastases. Preclinical studies have shown that primary tumors can release exosomes that establish premetastatic niches, thereby facilitating the development of subsequent lung 22 and lymph node 23 metastases. Therefore, even if distant metastases have completely disappeared, if the primary tumor remains, there is a risk of forming a new metastatic niche and redeveloping metastases. Previous trials evaluating primary tumor resection in MBC have not specifically addressed cases with complete metastatic remission. This case showed the possibility of long-term disease control via a multimodal approach, by combining systemic therapy, which can achieve metastatic remission, and surgical intervention, which can eradicate residual tumor cells. In the current case, the patient experienced manageable adverse effects, including grade 2 hematologic toxicity and transient proteinuria. Treatment modifications ensured continued therapy while decreasing complications. At 54 months post-treatment initiation, the patient remained disease-free, thereby emphasizing the potential efficacy and tolerability of the regimen. Conclusion This case provided evidence showing that the combination of bevacizumab, paclitaxel, and fulvestrant might be feasible for achieving long-term disease-free status in patients with hormone receptor-positive, HER2-negative unresectable inflammatory MBC. Nevertheless, further research should be performed to validate this approach and explore its application to a broader patient population. Declarations Ethics Approval and Consent to Participate The need for ethical approval for this case report was waived by the Ethics Committee of Meiwa Hospital, Nishinomiya, Hyogo, Japan, in accordance with the institutional guidelines. All procedures were conducted in accordance with the ethical standards of Meiwa Hospital. This study was conducted in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. The patient provided written informed consent prior to the initiation of treatment. Consent for Publication The patient provided written informed consent for publication. Data availability All data generated or analyzed during this study are included in this published article. Funding statement Not applicable Competing interests The authors declare that they have no competing interests. References Smith, I. Goals of treatment for patients with metastatic breast cancer. Semin. Oncol. 33, 2–5 (2006). Cardoso, F. et al. 5th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 5). Ann. Oncol. 31, 1623–1649 (2020). Grinda, T. et al. Evolution of overall survival and receipt of new therapies by subtype among 20446 metastatic breast cancer patients in the 2008–2017 ESME cohort. ESMO Open 6, 1–12 (2021). Kleer, C. G., van Golen, K. L. & Merajver, S. D. Molecular biology of breast cancer metastasis inflammatory breast cancer: clinical syndrome and molecular determinants. Breast Cancer Res. 2, 423–429 (2000). Dano, D. et al. Metastatic inflammatory breast cancer: survival outcomes and prognostic factors in the national, multicentric, and real-life French cohort (ESME). ESMO Open 6, 1–9 (2021). Matro, J. M. et al. Inflammatory breast cancer management in the National Comprehensive Cancer Network (NCCN): the disease, recurrence pattern, and the outcome. Clin. Breast Cancer 15, 1–7 (2015). Fouad, T. M. et al. Overall survival differences between patients with inflammatory and noninflammatory breast cancer presenting with distant metastasis at diagnosis. Breast Cancer Res. Treat. 152, 407–416 (2015). Miller, K. et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N. Engl. J. Med. 357, 2666–2676 (2007). Robertson, J. F. R. et al. Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cancer (FALCON): an international, randomized, double-blind, phase 3 trial. Lancet 388, 2997–3005 (2016). Martín, M. et al. Evaluating the addition of bevacizumab to endocrine therapy as first-line treatment for hormone-receptor positive metastatic breast cancer: a pooled-analysis from the LEA (GEICAM/2006-11_GBG51) and CALGB 40503 (Alliance) trials. Eur. J. Cancer 117, 91–98 (2019). Yardley, D. A. et al. Hormonal therapy plus bevacizumab in postmenopausal patients with hormone receptor-positive metastatic breast cancer: a phase II trial of the Sarah Cannon Oncology Research Consortium. Clin. Breast Cancer 11, 146–152 (2011). Ikeda, H. et al. Combination treatment with fulvestrant and various cytotoxic agents (doxorubicin, paclitaxel, docetaxel, vinorelbine, and 5-fluorouracil) has a synergistic effect in estrogen receptor-positive breast cancer. Cancer Sci. 102, 2038–2042 (2011). Patel, S. A. et al. Estrogen promotes resistance to bevacizumab in murine models of NSCLC. J. Thorac. Oncol. 16, 2051–2064 (2021). Liang, Y., Brekken, R. A. & Hyder, S. M. Vascular endothelial growth factor induces proliferation of breast cancer cells and inhibits the antiproliferative activity of antihormones. Endocr. Relat. Cancer 13, 905–919 (2006). Yoshiji, H. et al. Expression of vascular endothelial growth factor, its receptor, and other angiogenic factors in human breast cancer. Cancer Res. 56, 2013–2016 (1996). Tan, W. W. et al. N0539 phase II trial of fulvestrant and bevacizumab in patients with metastatic breast cancer previously treated with an aromatase inhibitor: a North Central Cancer Treatment Group (now Alliance) trial. Ann. Oncol. 24, 2548–2554 (2013). Martín, M. et al. Phase III trial evaluating the addition of bevacizumab to endocrine therapy as first-line treatment for advanced breast cancer: the Letrozole/Fulvestrant and Avastin (LEA) study. J. Clin. Oncol. 33, 1045–1052 (2015). Ikeda, H. et al. The estrogen receptor influences microtubule-associated protein tau (MAPT) expression and the selective estrogen receptor inhibitor fulvestrant downregulates MAPT and increases the sensitivity to taxane in breast cancer cells. Breast Cancer Res. 12, R43 (2010). Soran, A. et al. Randomized trial comparing locoregional resection of primary tumor with no surgery in stage IV breast cancer at presentation (Protocol MF07-01): a study of the Turkish Federation of the National Societies for Breast Diseases. Breast J. 15, 399–403 (2009). Fitzal, F. et al. Impact of breast surgery in primary metastasized breast cancer: outcomes of the prospective randomized phase III ABCSG-28 POSYTIVE trial. Ann. Surg. 269, 1163–1169 (2019). Badwe, R. et al. Locoregional treatment versus no treatment of the primary tumor in metastatic breast cancer: an open-label randomized controlled trial. Lancet Oncol. 16, 1380–1388 (2015). Hoshino, A. et al. Tumor exosome integrins determine organotropic metastasis. Nature 19, 329–335 (2015). Hood, J. L. et al. Exosomes released by melanoma cells prepare sentinel lymph nodes for tumor metastasis. Cancer Res. 71, 3792–3801 (2011). Additional Declarations No competing interests reported. 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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-6157011","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":442347489,"identity":"1f931b85-b699-4626-a42a-a5322361429e","order_by":0,"name":"Masahiro Kishimoto","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA/klEQVRIiWNgGAWjYBACCWYGNoYEIIOfgYGZIcGAwQAqwUZYi2Qb0VpgkgbHgFpANEGHSbazP3vwMMfO3vh+82ODBwUMxrozEhg//GDgy8OlRZqZx9wgcVty4rZjbMYJQIeZmd1IYJbsYWArxqVFjpmHTSJxG3OC2TEG4wNALTZALQzSQOcmNuDUwv4MqKXe3riN/TNMC/NvfFqkmRnMgFoOM25g44E7jA2vLZLNPCAtxxNnHMspNkgwkDA2O/OwzbLHALdfJM4ffyb5c1u1PX/z8c2SP/7YGG47nnz4xo+KYzhDDMMIIGZsAEVTArFa4KCGdC2jYBSMglEwXAEAtjZMezl6zBAAAAAASUVORK5CYII=","orcid":"","institution":"Kansai Medical University Medical Center","correspondingAuthor":true,"prefix":"","firstName":"Masahiro","middleName":"","lastName":"Kishimoto","suffix":""},{"id":442347490,"identity":"169c84ae-9ff0-4116-b1e4-119142d9f1d1","order_by":1,"name":"Chisa Murazawa","email":"","orcid":"","institution":"Meiwa Hospital","correspondingAuthor":false,"prefix":"","firstName":"Chisa","middleName":"","lastName":"Murazawa","suffix":""},{"id":442347491,"identity":"e6474352-695f-46fb-ae11-df3932d41369","order_by":2,"name":"Ayako Sugihara","email":"","orcid":"","institution":"Meiwa Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ayako","middleName":"","lastName":"Sugihara","suffix":""}],"badges":[],"createdAt":"2025-03-04 20:38:11","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6157011/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6157011/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":80818693,"identity":"99dd652c-dcb2-43e2-9657-008f842146d3","added_by":"auto","created_at":"2025-04-17 11:49:53","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":132823,"visible":true,"origin":"","legend":"\u003cp\u003eThe changes in the local findings of the chest are shown. a The pre-treatment clinical presentation was extensive erythema extending from both breasts to the upper abdomen, which is indicative of bilateral inflammatory breast cancer; b Post-radiation image showing persistent erythema despite a reduction in inflammatory changes, indicating incomplete resolution; c All excised skin margins were cancer-negative based on the intraoperative rapid histopathological diagnosis, and the inflammatory breast cancer lesion that had metastasized to both breasts and the bilateral axillary lymph nodes could be completely resected; d Local findings after 54 months of treatment, following local radical resection and rectus abdominis skin flap transplantation. Complete resolution of erythema and maintenance of the disease-free status are shown. The red arrow indicates the site of the full-thickness skin graft from the thigh.\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6157011/v1/21cc8a7725df77a13ff9def0.jpeg"},{"id":80818686,"identity":"53e0720d-f512-4406-b01e-b76ebc6cab26","added_by":"auto","created_at":"2025-04-17 11:49:52","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":166686,"visible":true,"origin":"","legend":"\u003cp\u003eA contrast-enhanced computed tomography (CT) scan image of the neck and chest.a Pre-treatment CT scan revealing over 8,000 pulmonary metastatic lesions, which is a characteristic finding of advanced-stage metastatic breast cancer; b Pre-treatment CT scan showing cervical lymph node metastases. The red arrow indicates right cervical lymph node metastasis; c Pre-treatment CT scan illustrating mediastinal lymph node metastases. The red arrow indicates mediastinal lymph node metastasis; d Post-treatment CT scan revealing the complete resolution of pulmonary metastases; e Post-treatment CT scan showing the absence of cervical lymph node metastases; f Post-treatment CT scan confirming the resolution of mediastinal lymph node metastases.\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6157011/v1/1032108234bc0159a697d66d.jpeg"},{"id":80819727,"identity":"e11c4b7f-56b2-4181-bede-40dc2f52a4d1","added_by":"auto","created_at":"2025-04-17 11:57:52","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":82208,"visible":true,"origin":"","legend":"\u003cp\u003eThe trends in the tumor markers breast cancer antigen 225 (BCA225) and cancer antigen 15-3 (CA15-3) in response to bevacizumab, paclitaxel, and fulvestrant are shown. The 15-3 levels continued to decrease immediately after treatment initiation, and the BCA225 levels increased briefly and then decreased significantly. The BCA225 and CA15-3 levels did not change from the period immediately after surgery to the present day.\u003c/p\u003e","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6157011/v1/bb2ea17d0538b7f7a5865dcc.jpeg"},{"id":83934819,"identity":"ced13599-f386-4bd1-ac03-6d8584b2e8d1","added_by":"auto","created_at":"2025-06-04 16:08:37","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":669799,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6157011/v1/bc692f58-ff82-4003-a031-2d770e1f2d7f.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Complete Remission and Radical Resection of Metastatic Inflammatory Breast Cancer Using Bevacizumab, Paclitaxel, and Fulvestrant","fulltext":[{"header":"Introduction","content":"\u003cp\u003eMetastatic breast cancer (MBC) has traditionally been considered incurable, with treatment goals focused on palliation and prolongation of survival \u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. The median overall survival (OS) of patients with hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer is 44.8 months \u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. Inflammatory breast cancer is an aggressive type of breast cancer characterized by rapid progression and poor prognosis \u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. The survival rates of patients with metastatic inflammatory breast cancer are poor, with a median OS of 26.0\u0026ndash;28.4 months \u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. The combined use of paclitaxel, a taxane-based anticancer drug, and bevacizumab, a humanized monoclonal antibody that targets all isoforms of vascular endothelial growth factor (VEGF)-A, is associated with a better progression-free survival (PFS) compared with paclitaxel alone. However, such treatment did not improve OS \u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e, and the complete response (CR) rate was low at 4%. Fulvestrant, a selective estrogen receptor degrading agent, improves PFS compared to anastrozole, an aromatase inhibitor. Although the CR rate for both fulvestrant and anastrozole was 3%, fulvestrant did not improve the CR rate. \u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. The combination of endocrine therapy and bevacizumab was well tolerated and associated with a superior PFS compared with endocrine therapy alone \u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. However, the CR rate was low at 5% \u003csup\u003e11\u003c/sup\u003e. In vitro and in vivo studies have reported the combined effects of fulvestrant and chemotherapeutic agents, particularly docetaxel, a taxane-based anticancer drug \u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. However, there are no reports about its clinical combination effects.\u003c/p\u003e \u003cp\u003eHerein, we present a case in which the combination of bevacizumab, paclitaxel, and fulvestrant resulted in the disappearance of all distant metastatic lesions, thereby enabling the radical resection of bilateral inflammatory breast cancer and achieving a long-term disease-free status.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eCase history and presentation\u003c/p\u003e \u003cp\u003eIn June 2020, a 65-year-old female patient presented with extensive erythema extending from both breasts to the upper abdomen (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea). Pathological evaluation revealed invasive ductal carcinoma of the bilateral breasts (pT4d, Ki-67 index of 50%) with dermal lymphatic invasion, which is consistent with inflammatory breast cancer. The tumors were estrogen receptor-positive (100%), progesterone receptor-positive (80%) and HER2-negative (1+). Contrast-enhanced computed tomography (CT) scan revealed over 8,000 pulmonary, cervical, mediastinal (Figs.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea, b and c), supraclavicular, infraclavicular, and axillary lymph node metastatic lesions. The patient had a history of type 2 diabetes and hypertension, with baseline blood glucose level at 256 mg/dL, hemoglobin A1C level at 8.1% and triglyceride level at 172 mg/dL. Her body mass index was 30 kg/m\u003csup\u003e2\u003c/sup\u003e. Urinalysis showed glycosuria (+\u0026thinsp;4), proteinuria (\u0026plusmn;) and hematuria (+\u0026thinsp;2).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eManagement\u003c/p\u003e \u003cp\u003eSystemic therapy was initiated with bevacizumab (10 mg/kg intravenously on days 1 and 15 every 4 weeks) and paclitaxel (80 mg/m\u0026sup2; intravenously on days 1, 8, and 15 every 4 weeks), combined with fulvestrant (500 mg intramuscularly on days 1, 15, and 29, then every 28 days). After 1 month, the treatment was interrupted as the patient had mild interstitial pneumonia caused by the coronavirus disease 2019. However, it was resumed after the patient recovered without significant residual symptoms.\u003c/p\u003e \u003cp\u003eAt 11 months post-treatment initiation, a CT scan revealed a significant reduction or disappearance of all pulmonary and lymph node metastatic lesions. The level of the tumor marker breast cancer antigen 225 continuously declined from baseline levels up to the time of surgery. Meanwhile, the cancer antigen 15\u0026thinsp;\u0026minus;\u0026thinsp;3 levels initially increased after treatment initiation but subsequently decreased significantly before surgery (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eAdverse events and treatment adjustments\u003c/p\u003e \u003cp\u003eThe hematologic adverse events included grade 2 leukopenia, neutropenia, lymphopenia, and anemia. Further, grade 1 elevations in aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyl transpeptidase levels were observed. The paclitaxel dosing was reduced by 15% on one occasion. As proteinuria progressed to 3+, bevacizumab and paclitaxel were discontinued. The patient was later treated with eribulin (1.4 mg/m\u0026sup2; intravenously on days 1 and 8 every 3 weeks) at a reduced dose (from 39\u0026ndash;13% of the full dose) for two cycles. Thereafter, proteinuria improved to \u0026plusmn;\u0026thinsp;within 3 weeks of treatment discontinuation.\u003c/p\u003e \u003cp\u003eRadiation therapy\u003c/p\u003e \u003cp\u003eThe combination of bevacizumab, paclitaxel, and fulvestrant resulted in the improvement of inflammatory breast cancer in both sides of the chest. However, erythema persisted. Therefore, during eribulin treatment, radiation therapy was administered to both chest walls at 2 Gy per fraction for a total of 25 fractions, with a total dose of 50 Gy. Nevertheless, the erythema did not completely resolve (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb).\u003c/p\u003e \u003cp\u003eSurgical intervention\u003c/p\u003e \u003cp\u003eDespite the reduction in erythema, residual skin changes persisted, requiring bilateral mastectomy, extensive skin excision, and lymph node dissection at 12 months post-treatment initiation. The skin excision margins were histologically evaluated in 2-cm sections (with a total of 52 specimens). Residual cancer was found in 33 sections, and additional excision was performed until all the margins were cancer-free (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ec). The wound was then closed using a rectus abdominis skin flap. Skin engraftment was good except in a small area on the upper left lateral side. After 1 month, the skin was harvested from the left thigh and grafted to the left upper lateral side, and the remaining area also had good skin grafting. The excised specimen contained diffuse residual invasive ductal carcinoma extending from the subcutaneous tissue to the dermis (longest diameter: 48 cm). Tumor cell infiltration was observed in the axillary fat tissue bilaterally. However, the lymph nodes presented with coagulative necrosis without viable tumor cells. Notably, the residual tumor transformed into a triple-negative phenotype (ER\u0026minus;, PgR\u0026minus;, HER2\u0026thinsp;\u0026minus;\u0026thinsp;and Ki-67 of 1%). The primary tumor, which had ultimately metastasized to both sides of the chest, was completely resected.\u003c/p\u003e \u003cp\u003eLong-term outcomes\u003c/p\u003e \u003cp\u003eFulvestrant therapy was resumed on postoperative day 15, followed by oral doxifluridine (800 mg/day), a prodrug of 5-fluorouracil, and cyclophosphamide (50 mg/day), an alkylating agent, on postoperative day 23. At 54 months post-treatment initiation, a CT scan confirmed sustained complete remission of distant metastases (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ed, e, and f). There was no local recurrence 54 months after the start of treatment and 42 months after surgery (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ed). Following surgery, the blood concentration of the tumor marker cancer antigen 15\u0026thinsp;\u0026minus;\u0026thinsp;3 continued to decline, and breast cancer antigen 225, which initially increased after treatment initiation, also showed a sustained decrease. This trend persisted, with both markers remaining at low levels up to the present day (42 months post-surgery), consistent with the patient\u0026rsquo;s ongoing disease-free status (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study found two important clinical issues. The combination of bevacizumab, paclitaxel, and fulvestrant achieved complete remission of pulmonary and distant lymph node metastases in hormone receptor-positive, HER2-negative breast cancer. Even in the case of metastatic bilateral inflammatory breast cancer, long-term disease-free survival was achieved using the combination of these drugs, followed by curative resection of the primary tumor after complete remission of distant metastases and shrinkage of the primary lesion.\u003c/p\u003e \u003cp\u003eFirst, the combination of bevacizumab, paclitaxel, and fulvestrant achieved complete remission of pulmonary and distant lymph node metastases. Compared with paclitaxel alone, the combination of paclitaxel and bevacizumab significantly prolonged PFS and increased the objective response rate. However, it did not improve OS \u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. In a preclinical study using a human xenograft model of non\u0026ndash;small-cell lung cancer, estrogen induced resistance to bevacizumab \u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. However, blockade of the estrogen receptor pathway with fulvestrant can restore treatment sensitivity to bevacizumab in cases of estrogen induced resistance to bevacizumab, regardless of breast cancer type. In another preclinical study using breast cancer cell lines, VEGF stimulated the growth of VEGF receptor 2-positive tumor cells and overrides the growth-suppressive effects of anti-hormones via the expression and activity of Bcl-2 \u003csup\u003e14\u003c/sup\u003e. Based on an analysis of the VEGF gene expression in human breast cancer, it was overexpressed in all 18 cancer tissues assessed compared with adjacent non-tumor tissues \u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. High VEGF levels in breast tumor tissues are associated with decreased response to anti-estrogen therapy in metastatic conditions \u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. Based on these results, the combination of bevacizumab and fulvestrant can enhance the therapeutic effect of the drugs. In phase II clinical trials, the combination of bevacizumab and fulvestrant was well tolerated, and the toxicity profile was consistent with the known toxicity profile of each single agent \u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. In a phase III clinical trial, the use of combined bevacizumab and endocrine as the first-line treatment did not significantly increase PFS or OS in women with advanced-stage breast cancer \u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. However, in a pooled analysis, the addition of bevacizumab to endocrine therapy increased the overall PFS, but not OS \u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. In a preclinical study, combination treatment with fulvestrant and taxanes in vitro exhibited synergistic effects in estrogen receptor-positive breast cancer cell lines \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. In vivo, a combination of fulvestrant and docetaxel had a synergistic effect on tumor growth \u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. The synergistic effect of these drug combinations can be attributed to the downregulation of the chemoresistance factors Bcl2 and the microtubule-associated protein tau caused by fulvestrant. There are no clinical trials on the combination therapy of bevacizumab, paclitaxel, and fulvestrant. To the best of our knowledge, this case provides the first clinical evidence supporting the combined use of these drugs.\u003c/p\u003e \u003cp\u003eSecond, even in the case of metastatic bilateral inflammatory breast cancer, long-term disease-free survival was achieved using the combination of these drugs, followed by curative resection of the primary tumor after complete remission of distant metastases and shrinkage of the primary lesion. There are several clinical trials on the resection of the primary site for stage IV breast cancer. Previous studies on the resection of the primary site before systemic treatment have different results, particularly in terms of extending OS \u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e, \u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. However, the OS did not improve with the resection of the primary site after systemic treatment when distant metastases persist \u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. However, to date, there are no clinical trials examining the resection of the primary site after the disappearance of distant metastases. Preclinical studies have shown that primary tumors can release exosomes that establish premetastatic niches, thereby facilitating the development of subsequent lung \u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e and lymph node \u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e metastases. Therefore, even if distant metastases have completely disappeared, if the primary tumor remains, there is a risk of forming a new metastatic niche and redeveloping metastases. Previous trials evaluating primary tumor resection in MBC have not specifically addressed cases with complete metastatic remission. This case showed the possibility of long-term disease control via a multimodal approach, by combining systemic therapy, which can achieve metastatic remission, and surgical intervention, which can eradicate residual tumor cells.\u003c/p\u003e \u003cp\u003eIn the current case, the patient experienced manageable adverse effects, including grade 2 hematologic toxicity and transient proteinuria. Treatment modifications ensured continued therapy while decreasing complications. At 54 months post-treatment initiation, the patient remained disease-free, thereby emphasizing the potential efficacy and tolerability of the regimen.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis case provided evidence showing that the combination of bevacizumab, paclitaxel, and fulvestrant might be feasible for achieving long-term disease-free status in patients with hormone receptor-positive, HER2-negative unresectable inflammatory MBC. Nevertheless, further research should be performed to validate this approach and explore its application to a broader patient population.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthics Approval and Consent to Participate\u003c/p\u003e\n\u003cp\u003eThe need for ethical approval for this case report was waived by the Ethics Committee of Meiwa Hospital, Nishinomiya, Hyogo, Japan, in accordance with the institutional guidelines.\u0026nbsp;\u003cbr\u003e\u0026nbsp;All procedures were conducted in accordance with the ethical standards of Meiwa Hospital.\u0026nbsp;\u003cbr\u003e\u0026nbsp;This study was conducted in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.\u0026nbsp;\u003cbr\u003e\u0026nbsp;The patient provided written informed consent prior to the initiation of treatment.\u003c/p\u003e\n\u003cp\u003eConsent for Publication\u003c/p\u003e\n\u003cp\u003eThe patient provided written informed consent for publication.\u003c/p\u003e\n\u003cp\u003eData availability\u003cbr\u003e\u0026nbsp;All data generated or analyzed during this study are included in this published article.\u003c/p\u003e\n\u003cp\u003eFunding statement\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003eCompeting interests\u003cbr\u003e\u0026nbsp;The authors declare that they have no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSmith, I. 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Locoregional treatment versus no treatment of the primary tumor in metastatic breast cancer: an open-label randomized controlled trial. Lancet Oncol. 16, 1380\u0026ndash;1388 (2015).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHoshino, A. et al. Tumor exosome integrins determine organotropic metastasis. Nature 19, 329\u0026ndash;335 (2015).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHood, J. L. et al. Exosomes released by melanoma cells prepare sentinel lymph nodes for tumor metastasis. Cancer Res. 71, 3792\u0026ndash;3801 (2011).\u003c/span\u003e\u003c/li\u003e\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-6157011/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6157011/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eIn most cases, unresectable metastatic breast cancer (MBC) is incurable. We report a case of bilateral inflammatory breast cancer with multiple pulmonary and distant lymph node metastatic lesions, achieving complete remission of distant metastases and curative resection of the primary lesions through combined regimen of bevacizumab, paclitaxel, and fulvestrant. A 65-year-old female patient presented with hormone receptor-positive, HER2-negative breast cancer with extensive inflammatory changes in the bilateral breast and skin, accompanied by multiple pulmonary and distant lymph node metastatic lesions. Treatment with bevacizumab, paclitaxel, and fulvestrant, resulted in complete remission of distant metastases and primary lesion reduction, enabling curative resection. At 54 months from treatment initiation and 42 months post-surgery, the patient remained disease-free. Based on this case, the combined use of bevacizumab, paclitaxel, and fulvestrant might eradicate distant metastases and facilitate curative resection in unresectable primary tumors. This treatment should be considered in patients with inoperable MBC.\u003c/p\u003e","manuscriptTitle":"Complete Remission and Radical Resection of Metastatic Inflammatory Breast Cancer Using Bevacizumab, Paclitaxel, and Fulvestrant","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-17 11:49:47","doi":"10.21203/rs.3.rs-6157011/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":"1a217a34-8943-4ec3-bf7a-e3d3d1be155e","owner":[],"postedDate":"April 17th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-06-04T16:08:17+00:00","versionOfRecord":[],"versionCreatedAt":"2025-04-17 11:49:47","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6157011","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6157011","identity":"rs-6157011","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}