Pathologic Complete Response in Triple Negative Breast Cancer Treated with Anthracycline Free Regimen: a case report

Pathologic Complete Response in Triple Negative Breast Cancer Treated with Anthracycline Free Regimen: a case report | 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 Pathologic Complete Response in Triple Negative Breast Cancer Treated with Anthracycline Free Regimen: a case report Francesca Piazza, Giulia Scartabellati, Laura Moretti, Marta Laganà, and 11 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6734680/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 Triple-negative breast cancer (TNBC) is a highly aggressive malignancy with limited therapeutic options and elevated mortality rates. Chemo-immunotherapy according to the KEYNOTE-522 has established a new standard of care in the neoadjuvant setting, due to high rates of pathological complete response (pCR) and improved survival outcomes. Considering the efficacy scenario, it is essential to explore whether and when treatment de-escalation may be feasible to mitigate toxicity. We report the clinical case of a 54-year-old Caucasian woman with high-risk cT4a cN0 TNBC who achieved both clinical and pathological complete response despite early discontinuation of neoadjuvant therapy. Due to anthracycline extravasation, four cycles of anthracyclines, cyclophosphamide, and pembrolizumab were omitted. This case suggests a potential role for de-escalated regimens in selected patients. However, the absence of reliable predictive biomarkers limits appropriate patient selection. Further investigation is warranted to identify which patients could safely benefit from reduced-intensity approaches without compromising outcomes. breast cancer neoadjuvant treatment immunotherapy Figures Figure 1 Figure 2 Introduction Triple-negative breast cancer (TNBC) is defined by the absence of expression of oestrogen (ER) and progesterone (PR) receptors, and human epidermal growth factor receptor 2 (HER2) overexpression and/or gene amplification. It accounts for up to 15% of all breast malignancies and, despite early-stage diagnosis, TNBC is often characterized by a high propensity for early recurrence and elevated mortality rates [1]. The KEYNOTE-522 study has established a new standard of care for an increasing subset of patients with stage II or III TNBC [2–4]. Indeed, the addition of pembrolizumab to neoadjuvant chemotherapy with carboplatin/paclitaxel followed by anthracycline-based chemotherapy (AC/EC) resulted in a significant improvement in pathological complete response (pCR) rates, increasing from 51.2% to 64.8%, with an absolute difference of 13.6% (p<0.001). Moreover, the addition of immunotherapy conferred a clinically meaningful benefit in long-term outcomes, with a 36-month event-free survival (EFS) rate of 84% in the pembrolizumab group compared to 77% in the placebo group, corresponding to a 37% reduction in the risk of disease recurrence or progression (HR 0.63, 95% CI 0.48–0.82) [3]. Additionally, five-year overall survival (OS) was significantly improved, reaching 86.6% (95% CI, 84.0–88.8) with pembrolizumab versus 81.7% (95% CI, 77.5–85.2) in the placebo arm, further reinforcing the long-term efficacy of immune checkpoint inhibition in the early-stage TNBC setting [4]. After a median follow-up of 75.1 months, the majority of treatment-related adverse events were observed during the neoadjuvant phase and were predominantly associated with chemotherapy [4]. The most frequently reported toxicities included nausea, vomiting, fatigue, neutropenia, febrile neutropenia, and cardiac disorders, which were possibly attributable to the administration of anthracyclines and cyclophosphamide [4]. These agents are known to be associated with severe long-term toxicities, including cardiotoxicity, secondary malignancies, and infertility [5,6]. Considering the efficacy and safety scenario described so far, it is essential to explore whether and when treatment de-escalation may be feasible in order to mitigate toxicity. However, the KEYNOTE-522 trial was not designed to evaluate the impact of adjuvant pembrolizumab or the feasibility of chemotherapy de-escalation, particularly in patients achieving pCR, leaving these questions unresolved. To tailor therapy to individual patient needs, it would be crucial to incorporate patient age, comorbidities, clinical characteristics, and biomarker profiles into a personalized treatment approach. The absence of reliable biomarkers to identify TNBC patients who would derive the greatest benefit from immune checkpoint inhibitors underscores the urgent need for predictive strategies to optimize patient selection and treatment personalization. We report a clinical case of a patient with early-stage, high-risk TNBC who achieved both clinical and pathological complete response despite the omission of four cycles of anthracyclines, cyclophosphamide, and pembrolizumab. This case prompts a discussion on the potential role of treatment de-escalation strategies in selected patient populations. Case report In February 2024, a 54-year-old Caucasian woman detected a palpable mass in the right breast during self-examination. Initial breast ultrasound (US) and mammography, followed by magnetic resonance imaging (MRI), identified a neoplastic lesion measuring 78 × 53 × 68 mm in the lower outer quadrant of the right breast, with infiltration of the pectoralis muscle and extension into the chest wall. No pathological lymphadenopathies were observed. Core needle biopsies and histological analysis confirmed a high-grade, poorly differentiated infiltrating ductal carcinoma. Immunohistochemistry (IHC) revealed the absence of oestrogen and progesterone receptors (0% and < 1%, respectively) and no HER2 overexpression (IHC score 0). The tumor displayed a high proliferative index (Ki67, 65%) and low tumor-infiltrating lymphocytes (TILs) with a score of 5%. Further assessment with a computed tomography (CT) scan of the brain, chest, abdomen, and pelvis showed no distant metastasis. The tumor was staged as cT4a cN0 cM0, and histologically classified as TNBC. Therefore, considering the patient's overall health status, disease extent, and risk profile, in April 2024, the multidisciplinary team recommended neoadjuvant treatment according to the Keynote-522 regimen. After 24 weeks, the patient had completed four cycles of weekly carboplatin, paclitaxel and pembrolizumab without any significant adverse toxicity. The interim breast US demonstrated a substantial reduction in tumor size (22 mm compared to the initial 78 mm). Given this remarkable response, in August 2024, the patient transitioned to the second phase of neoadjuvant chemotherapy. However, shortly after the initiation of the first infusion, epirubicin extravasation occurred from the peripherally inserted central catheter-PORT (PICC-port). The extravasated drug was promptly removed mechanically, followed by topical application of dimethyl sulfoxide (DMSO). Additionally, dexrazoxane was administered over three consecutive days to mitigate tissue damage. The tissue damage progressively worsened over days to weeks, resulting in pain, thrombosis, oedema and functional impairment. (Fig. 1 ). The case was discussed within a multidisciplinary team, which concluded that, given the risk of infection, potentially exacerbated by chemotherapy-induced neutropenia, and the favourable objective response, neoadjuvant treatment should be discontinued, and the patient should be addressed to surgery. A breast MRI, performed before surgery, showed a radiological complete response (Fig. 2 ). In September 2024, the patient underwent right mastectomy with sentinel lymph node biopsy (SLNB) surgery. The surgical specimen confirmed the pCR (ypT0, ypN0). After surgery, given the resolution of the extravasation-related injury (Fig. 1 ), the exceptional treatment response, and the absence of prior immune-related adverse events, the patient initiated the adjuvant phase with pembrolizumab in October 2024, which is ongoing at the time of this report. Discussion KEYNOTE-522 represents the first phase III, prospective, randomized controlled trial demonstrating statistically significant improvements in pCR, EFS and OS with neoadjuvant pembrolizumab plus chemotherapy in patients with early-stage TNBC in both the neoadjuvant and adjuvant treatment settings [2–4]. The greatest magnitude of benefit from the addition of pembrolizumab was observed in patients with stage III disease, as was the case for our patient. Despite receiving a regimen of carboplatin, paclitaxel, and pembrolizumab alone in the neoadjuvant setting, pCR was achieved. This clinical case raises several questions, one of which is whether a de-escalated treatment approach omitting anthracyclines could be considered in patients with TNBC who exhibit a clinical complete response and how to appropriately identify such cases. Anthracyclines are well known to cause long-term cardiac side effects, including congestive heart failure and cardiomyopathy [6] and secondary leukemia, including acute myeloid leukemia and myelodysplastic syndrome [5]. Anthracycline-free regimens of carboplatin and taxane without immunotherapy have been investigated as a de-escalating strategy in neoadjuvant treatment of early TNBC demonstrating promising pCR rates [7,8]. The phase II clinical trial NeoPACT, which investigate the role of carboplatin and docetaxel plus pembrolizumab every 21 days for 6 cycles in patients who are not eligible for anthracycline-based regimens, showed encouraging results with a pCR rate of 58% [9]. Moreover, in this trial, treatment-related adverse events leading to the discontinuation of any trial drug were reported in 12% of patients, which is favourable compared to the 23% observed in the KEYNOTE-522 trial [3]. On the wave of these results, different trials are evaluating the efficacy of anthracycline-free chemotherapy in combination with immunotherapy, such as the SCARLET trial (Clinical trials.gov identifier: NCT05929768). Contrary to the de-escalation approach, a recent post-hoc analysis of the KEYNOTE-522 trial showed superior outcomes in patients who completed the full chemotherapy regimen compared to those who received less than the full course [10]. The pCR rate was lower in patients who could not complete full chemotherapy in both treatment groups, emphasizing the importance of completing the full treatment course and raising questions about the feasibility of treatment de-escalation, also due to the lack of biomarkers able to predict who will achieve pCR and who requires a more intensive chemotherapy regimen. However, it should be noted that this analysis does not provide insight into which part of the chemotherapy regimen was omitted [10]. Nonetheless, appropriate patient selection and thorough evaluation of the optimal treatment duration remain essential to limit long-term toxicities, especially in light of recent data from the KN522 trial indicating that the majority of adverse events occurred during the neoadjuvant phase of therapy [3]. To date there is a lack of biomarkers to guide the selection of TNBC patients, highlighting the need to identify responders to immune checkpoint inhibitors in advance. Indeed, the identification of stratifying factors, targets and biomarkers could lead to the identification of patients who may benefit from the de-escalation of neoadjuvant treatment. At present TILs density has been demonstrated to be an independent predictor of OS beyond clinicopathologic features and pathologic response in patients with TNBC treated both with anthracycline-free regimens [11] and anthracycline-containing neoadjuvant chemotherapy [12]. A recent real-world study indicates that elevated TIL levels are strongly correlated with pCR rates in 76 TNBC patients who received the KEYNOTE-522 regimen and could potentially serve as a biomarker for guiding treatment selection [13]. In the literature, a cut-off value of 30% has been proposed to distinguish between TIL-high and TIL-low groups, and this threshold has also been considered appropriate for use in potential chemotherapy de-escalation studies [14,15]. However, our patient achieved a pCR with an anthracycline-free regimen, despite baseline low TIL. In addition, as suggested by Sharma et al., other immune biomarkers could have a predictive role, such as the expression of genes involved in DNA damage immune response and genes involved in the tumor immune microenvironment [16]. Moreover, recent data suggest that radiomic signatures derived from multiparametric MRI images obtained early during neoadjuvant treatment could predict treatment response in patients with TNBC[17]. In the future, an adaptive clinical trial, as the I-SPY trial [18], combining imaging and biological biomarkers, could try to stratify patients addressed to neoadjuvant therapy for TNBC selecting those who could safely receive a de-escalation therapy [18]. To date, as in the case of our patient, tumor response monitoring in clinical practice is typically assessed through breast ultrasound, a safe and cost-effective procedure. However, due to the intrinsic limitations of this technique, it does not allow for optimal stratification of patients who have achieved a complete response to treatment. In the future, the use of multiple integrated modalities—such as in the I-SPY trial—could enable more accurate monitoring of treatment response and support a safe de-escalation strategy. However, the limitations related to costs and the burden on patients must also be considered. In conclusion, the KEYNOTE-522 trial demonstrated for the first time that the addition of immunotherapy can achieve unprecedented pCR and OS rates in TNBC. This raises the crucial question of whether such outcomes could be obtained with a less aggressive chemotherapy regimen. Our case report suggests that pCR can be achieved in the absence of anthracyclines, however a question remains open: could the inflammatory response triggered by the extravasation of epirubicin have enhanced the immune-mediated anti-tumor effect? While we acknowledge the need for further studies to validate treatment de-escalation strategies in early-stage disease, this patient’s unique clinical course raises the possibility that unintended immunologic stimulation may have contributed to the observed outcome—highlighting the complexity and unpredictability of host–tumor interactions. 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. 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 Data availability: not applicable References Lee YM, Oh MH, Go JH, Han K, Choi SY. Molecular subtypes of triple-negative breast cancer: understanding of subtype categories and clinical implication. Genes and Genomics 2020. https://doi.org/10.1007/s13258-020-01014-7. Ali MA, Aiman W, Shah SS, Hussain M, Kashyap R. Efficacy and safety of pembrolizumab based therapies in triple-negative breast cancer: A systematic review of clinical trials. Crit Rev Oncol Hematol 2021. https://doi.org/10.1016/j.critrevonc.2020.103197. 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Randomized Phase II Trial of Anthracycline-free and Anthracycline-containing Neoadjuvant Carboplatin Chemotherapy Regimens in Stage I–III Triple-negative Breast Cancer (NeoSTOP). Clin Cancer Res 2021;27:975–82. https://doi.org/10.1158/1078-0432.CCR-20-3646. Gluz O, Nitz U, Liedtke C, Christgen M, Grischke EM, Forstbauer H, et al. Comparison of neoadjuvant Nab-paclitaxel1carboplatin vs nab-paclitaxel1gemcitabine in triple-negative breast cancer: Randomized WSG-ADAPT-TN trial results. J Natl Cancer Inst 2018;110:628–37. https://doi.org/10.1093/jnci/djx258. Sharma P, Stecklein SR, Yoder R, Staley JM, Schwensen K, O’Dea A, et al. Clinical and Biomarker Findings of Neoadjuvant Pembrolizumab and Carboplatin Plus Docetaxel in Triple-Negative Breast Cancer NeoPACT Phase 2 Clinical Trial. JAMA Oncol 2024. https://doi.org/10.1001/jamaoncol.2023.5033. Pusztai L, Denkert C, O’Shaughnessy J, Cortes J, Dent R, McArthur H, et al. 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High tumor infiltrating lymphocytes are significantly associated with pathological complete response in triple negative breast cancer treated with neoadjuvant KEYNOTE-522 chemoimmunotherapy. Breast Cancer Res Treat 2024;205:193–9. https://doi.org/10.1007/s10549-023-07233-2. Loi S, Michiels S, Adams S, Loibl S, Budczies J, Denkert C, et al. The journey of tumor-infiltrating lymphocytes as a biomarker in breast cancer: clinical utility in an era of checkpoint inhibition. Ann Oncol 2021. https://doi.org/10.1016/j.annonc.2021.07.007. Loi S, Salgado R, Adams S, Pruneri G, Francis PA, Lacroix-Triki M, et al. Tumor infiltrating lymphocyte stratification of prognostic staging of early-stage triple negative breast cancer. Npj Breast Cancer 2022. https://doi.org/10.1038/s41523-021-00362-1. Sharma P, Siddiqui BA, Anandhan S, Yadav SS, Subudhi SK, Gao J, et al. The next decade of immune checkpoint therapy. Cancer Discov 2021. https://doi.org/10.1158/2159-8290.CD-20-1680. Mohamed RM, Panthi B, Adrada B, Candelaria R, Guirguis MS, Yang W, et al. Abstract P6-01-06: Multi-Parametric MRI-Based Radiomics Models from Tumor and Peritumoral Regions as Potential Predictors of Treatment Response to Neoadjuvant Systemic Therapy in Triple Negative Breast Cancer Patients. Cancer Res 2023. https://doi.org/10.1158/1538-7445.sabcs22-p6-01-06. Wang H, Yee D. I-SPY 2: a Neoadjuvant Adaptive Clinical Trial Designed to Improve Outcomes in High-Risk Breast Cancer. Curr Breast Cancer Rep 2019. https://doi.org/10.1007/s12609-019-00334-2. 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. 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2","display":"","copyAsset":false,"role":"figure","size":142422,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eBreast MRI performed before and after neoadjuvant treatment.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6734680/v1/214d4aba4e8c1090d1bfa9b9.png"},{"id":88605404,"identity":"aeb525b8-a48b-47d4-bb06-98c1143ac3b7","added_by":"auto","created_at":"2025-08-08 08:39:44","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1012200,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6734680/v1/95f659e8-a2c8-49c4-8126-c98bc8c0f7d3.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003ePathologic Complete Response in Triple Negative Breast Cancer Treated with Anthracycline Free Regimen: a case report\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eTriple-negative breast cancer (TNBC) is defined by the absence of expression of oestrogen (ER) and progesterone (PR) receptors, and human epidermal growth factor receptor 2 (HER2) overexpression and/or gene amplification. It accounts for up to 15% of all breast malignancies and, despite early-stage diagnosis, TNBC is often characterized by a high propensity for early recurrence and elevated mortality rates [1].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe KEYNOTE-522 study has established a new standard of care for an increasing subset of patients with stage II or III TNBC [2\u0026ndash;4]. Indeed, the addition of pembrolizumab to neoadjuvant chemotherapy with carboplatin/paclitaxel followed by anthracycline-based chemotherapy (AC/EC) resulted in a significant improvement in pathological complete response (pCR) rates, increasing from 51.2% to 64.8%, with an absolute difference of 13.6% (p\u0026lt;0.001). Moreover, the addition of immunotherapy conferred a clinically meaningful benefit in long-term outcomes, with a 36-month event-free survival (EFS) rate of 84% in the pembrolizumab group compared to 77% in the placebo group, corresponding to a 37% reduction in the risk of disease recurrence or progression (HR 0.63, 95% CI 0.48\u0026ndash;0.82) [3]. Additionally, five-year overall survival (OS) was significantly improved, reaching 86.6% (95% CI, 84.0\u0026ndash;88.8) with pembrolizumab versus 81.7% (95% CI, 77.5\u0026ndash;85.2) in the placebo arm, further reinforcing the long-term efficacy of immune checkpoint inhibition in the early-stage TNBC setting [4].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAfter a median follow-up of 75.1 months, the majority of treatment-related adverse events were observed during the neoadjuvant phase and were predominantly associated with chemotherapy [4]. The most frequently reported toxicities included nausea, vomiting, fatigue, neutropenia, febrile neutropenia, and cardiac disorders, which were possibly attributable to the administration of anthracyclines and cyclophosphamide [4]. These agents are known to be associated with severe long-term toxicities, including cardiotoxicity, secondary malignancies, and infertility [5,6].\u003c/p\u003e\n\u003cp\u003eConsidering the efficacy and safety scenario described so far, it is essential to explore whether and when treatment de-escalation may be feasible in order to mitigate toxicity. However, the KEYNOTE-522 trial was not designed to evaluate the impact of adjuvant pembrolizumab or the feasibility of chemotherapy de-escalation, particularly in patients achieving pCR, leaving these questions unresolved.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTo tailor therapy to individual patient needs, it would be crucial to incorporate patient age, comorbidities, clinical characteristics, and biomarker profiles into a personalized treatment approach. The absence of reliable biomarkers to identify TNBC patients who would derive the greatest benefit from immune checkpoint inhibitors underscores the urgent need for predictive strategies to optimize patient selection and treatment personalization.\u003c/p\u003e\n\u003cp\u003eWe report a clinical case of a patient with early-stage, high-risk TNBC who achieved both clinical and pathological complete response despite the omission of four cycles of anthracyclines, cyclophosphamide, and pembrolizumab. This case prompts a discussion on the potential role of treatment de-escalation strategies in selected patient populations.\u003c/p\u003e"},{"header":"Case report","content":"\u003cp\u003eIn February 2024, a 54-year-old Caucasian woman detected a palpable mass in the right breast during self-examination. Initial breast ultrasound (US) and mammography, followed by magnetic resonance imaging (MRI), identified a neoplastic lesion measuring 78 \u0026times; 53 \u0026times; 68 mm in the lower outer quadrant of the right breast, with infiltration of the pectoralis muscle and extension into the chest wall. No pathological lymphadenopathies were observed.\u003c/p\u003e\u003cp\u003eCore needle biopsies and histological analysis confirmed a high-grade, poorly differentiated infiltrating ductal carcinoma. Immunohistochemistry (IHC) revealed the absence of oestrogen and progesterone receptors (0% and \u0026lt;\u0026thinsp;1%, respectively) and no HER2 overexpression (IHC score 0). The tumor displayed a high proliferative index (Ki67, 65%) and low tumor-infiltrating lymphocytes (TILs) with a score of 5%. Further assessment with a computed tomography (CT) scan of the brain, chest, abdomen, and pelvis showed no distant metastasis.\u003c/p\u003e\u003cp\u003eThe tumor was staged as cT4a cN0 cM0, and histologically classified as TNBC. Therefore, considering the patient's overall health status, disease extent, and risk profile, in April 2024, the multidisciplinary team recommended neoadjuvant treatment according to the Keynote-522 regimen.\u003c/p\u003e\u003cp\u003eAfter 24 weeks, the patient had completed four cycles of weekly carboplatin, paclitaxel and pembrolizumab without any significant adverse toxicity. The interim breast US demonstrated a substantial reduction in tumor size (22 mm compared to the initial 78 mm). Given this remarkable response, in August 2024, the patient transitioned to the second phase of neoadjuvant chemotherapy.\u003c/p\u003e\u003cp\u003eHowever, shortly after the initiation of the first infusion, epirubicin extravasation occurred from the peripherally inserted central catheter-PORT (PICC-port). The extravasated drug was promptly removed mechanically, followed by topical application of dimethyl sulfoxide (DMSO). Additionally, dexrazoxane was administered over three consecutive days to mitigate tissue damage. The tissue damage progressively worsened over days to weeks, resulting in pain, thrombosis, oedema and functional impairment. (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThe case was discussed within a multidisciplinary team, which concluded that, given the risk of infection, potentially exacerbated by chemotherapy-induced neutropenia, and the favourable objective response, neoadjuvant treatment should be discontinued, and the patient should be addressed to surgery. A breast MRI, performed before surgery, showed a radiological complete response (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). In September 2024, the patient underwent right mastectomy with sentinel lymph node biopsy (SLNB) surgery. The surgical specimen confirmed the pCR (ypT0, ypN0). After surgery, given the resolution of the extravasation-related injury (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e), the exceptional treatment response, and the absence of prior immune-related adverse events, the patient initiated the adjuvant phase with pembrolizumab in October 2024, which is ongoing at the time of this report.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eKEYNOTE-522 represents the first phase III, prospective, randomized controlled trial demonstrating statistically significant improvements in pCR, EFS and OS with neoadjuvant pembrolizumab plus chemotherapy in patients with early-stage TNBC in both the neoadjuvant and adjuvant treatment settings [2\u0026ndash;4]. The greatest magnitude of benefit from the addition of pembrolizumab was observed in patients with stage III disease, as was the case for our patient. Despite receiving a regimen of carboplatin, paclitaxel, and pembrolizumab alone in the neoadjuvant setting, pCR was achieved. This clinical case raises several questions, one of which is whether a de-escalated treatment approach omitting anthracyclines could be considered in patients with TNBC who exhibit a clinical complete response and how to appropriately identify such cases.\u003c/p\u003e\n\u003cp\u003eAnthracyclines are well known to cause long-term cardiac side effects, including congestive heart failure and cardiomyopathy [6] and secondary leukemia, including acute myeloid leukemia and myelodysplastic syndrome [5]. Anthracycline-free regimens of carboplatin and taxane without immunotherapy have been investigated as a de-escalating strategy in neoadjuvant treatment of early TNBC demonstrating promising pCR rates [7,8]. The phase II clinical trial NeoPACT, which investigate the role of carboplatin and docetaxel plus pembrolizumab every 21 days for 6 cycles in patients who are not eligible for anthracycline-based regimens, showed encouraging results with a pCR rate of 58% [9]. Moreover, in this trial, treatment-related adverse events leading to the discontinuation of any trial drug were reported in 12% of patients, which is favourable compared to the 23% observed in the KEYNOTE-522 trial [3]. On the wave of these results, different trials are evaluating the efficacy of anthracycline-free chemotherapy in combination with immunotherapy, such as the SCARLET trial (Clinical trials.gov identifier: NCT05929768).\u0026nbsp;Contrary to the de-escalation approach, a recent post-hoc analysis of the KEYNOTE-522 trial showed superior outcomes in patients who completed the full chemotherapy regimen compared to those who received less than the full course [10]. The pCR rate was lower in patients who could not complete full chemotherapy in both treatment groups, emphasizing the importance of completing the full treatment course and raising questions about the feasibility of treatment de-escalation, also due to the lack of biomarkers able to predict who will achieve pCR and who requires a more intensive chemotherapy regimen. However, it should be noted that this analysis does not provide insight into which part of the chemotherapy regimen was omitted [10].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNonetheless, appropriate patient selection and thorough evaluation of the optimal treatment duration remain essential to limit long-term toxicities, especially in light of recent data from the KN522 trial indicating that the majority of adverse events occurred during the neoadjuvant phase of therapy [3].\u003c/p\u003e\n\u003cp\u003eTo date there is a lack of biomarkers to guide the selection of TNBC patients, highlighting the need to identify responders to immune checkpoint inhibitors in advance. Indeed, the identification of stratifying factors, targets and biomarkers could lead to the identification of patients who may benefit from the de-escalation of neoadjuvant treatment. At present TILs density has been demonstrated to be an independent predictor of OS beyond clinicopathologic features and pathologic response in patients with TNBC treated\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003eboth with anthracycline-free regimens [11] and anthracycline-containing neoadjuvant chemotherapy [12]. A recent real-world study indicates that elevated TIL levels are strongly correlated with pCR rates in 76 TNBC patients who received the KEYNOTE-522 regimen and could potentially serve as a biomarker for guiding treatment selection [13]. In the literature, a cut-off value of 30% has been proposed to distinguish between TIL-high and TIL-low groups, and this threshold has also been considered appropriate for use in potential chemotherapy de-escalation studies [14,15].\u0026nbsp;However, our patient achieved a pCR with an anthracycline-free regimen, despite baseline low TIL. In addition, as suggested by Sharma et al., other immune biomarkers could have a predictive role, such as the expression of genes involved in DNA damage immune response and genes involved in the tumor immune microenvironment\u0026nbsp;[16].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMoreover, recent data suggest that radiomic signatures derived from multiparametric MRI images obtained early during neoadjuvant treatment could predict treatment response in patients with TNBC[17]. In the future, an adaptive clinical trial, as the I-SPY trial [18], combining imaging and biological biomarkers, could try to stratify patients addressed to neoadjuvant therapy for TNBC selecting those who could safely receive a de-escalation therapy [18]. To date, as in the case of our patient, tumor response monitoring in clinical practice is typically assessed through breast ultrasound, a safe and cost-effective procedure. However, due to the intrinsic limitations of this technique, it does not allow for optimal stratification of patients who have achieved a complete response to treatment. In the future, the use of multiple integrated modalities\u0026mdash;such as in the I-SPY trial\u0026mdash;could enable more accurate monitoring of treatment response and support a safe de-escalation strategy. However, the limitations related to costs and the burden on patients must also be considered.\u003c/p\u003e\n\u003cp\u003eIn conclusion, the KEYNOTE-522 trial demonstrated for the first time that the addition of immunotherapy can achieve unprecedented pCR and OS rates in TNBC. \u0026nbsp;This raises the crucial question of whether such outcomes could be obtained with a less aggressive chemotherapy regimen. Our case report suggests that pCR can be achieved in the absence of anthracyclines, however a question remains open: could the inflammatory response triggered by the extravasation of epirubicin have enhanced the immune-mediated anti-tumor effect? While we acknowledge the need for further studies to validate treatment de-escalation strategies in early-stage disease, this patient\u0026rsquo;s unique clinical course raises the possibility that unintended immunologic stimulation may have contributed to the observed outcome\u0026mdash;highlighting the complexity and unpredictability of host\u0026ndash;tumor interactions.\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. 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\n\u003cp\u003e\u003cstrong\u003eData availability:\u003c/strong\u003e not applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eLee YM, Oh MH, Go JH, Han K, Choi SY. Molecular subtypes of triple-negative breast cancer: understanding of subtype categories and clinical implication. Genes and Genomics 2020. https://doi.org/10.1007/s13258-020-01014-7.\u003c/li\u003e\n \u003cli\u003eAli MA, Aiman W, Shah SS, Hussain M, Kashyap R. Efficacy and safety of pembrolizumab based therapies in triple-negative breast cancer: A systematic review of clinical trials. Crit Rev Oncol Hematol 2021. https://doi.org/10.1016/j.critrevonc.2020.103197.\u003c/li\u003e\n \u003cli\u003eSchmid P, Cortes J, Dent R, Pusztai L, McArthur H, K\u0026uuml;mmel S, et al. Event-free Survival with Pembrolizumab in Early Triple-Negative Breast Cancer. N Engl J Med 2022. https://doi.org/10.1056/nejmoa2112651.\u003c/li\u003e\n \u003cli\u003eSchmid P, Cortes J, Dent R, McArthur H, Pusztai L, K\u0026uuml;mmel S, et al. Overall Survival with Pembrolizumab in Early-Stage Triple-Negative Breast Cancer. N Engl J Med 2024:1\u0026ndash;11. https://doi.org/10.1056/NEJMoa2409932.\u003c/li\u003e\n \u003cli\u003eRosenstock AS, Niu J, Giordano SH, Zhao H, Wolff AC, Chavez-MacGregor M. Acute myeloid leukemia and myelodysplastic syndrome after adjuvant chemotherapy: A population-based study among older breast cancer patients. Cancer 2018;124:899\u0026ndash;906. https://doi.org/10.1002/cncr.31144.\u003c/li\u003e\n \u003cli\u003eNishi M, Wang PY, Hwang PM. Cardiotoxicity of Cancer Treatments: Focus on Anthracycline Cardiomyopathy. Arterioscler Thromb Vasc Biol 2021. https://doi.org/10.1161/ATVBAHA.121.316697.\u003c/li\u003e\n \u003cli\u003eSharma P, Kimler BF, O\u0026rsquo;Dea A, Nye L, Wang YY, Yoder R, et al. Randomized Phase II Trial of Anthracycline-free and Anthracycline-containing Neoadjuvant Carboplatin Chemotherapy Regimens in Stage I\u0026ndash;III Triple-negative Breast Cancer (NeoSTOP). Clin Cancer Res 2021;27:975\u0026ndash;82. https://doi.org/10.1158/1078-0432.CCR-20-3646.\u003c/li\u003e\n \u003cli\u003eGluz O, Nitz U, Liedtke C, Christgen M, Grischke EM, Forstbauer H, et al. Comparison of neoadjuvant Nab-paclitaxel1carboplatin vs nab-paclitaxel1gemcitabine in triple-negative breast cancer: Randomized WSG-ADAPT-TN trial results. J Natl Cancer Inst 2018;110:628\u0026ndash;37. https://doi.org/10.1093/jnci/djx258.\u003c/li\u003e\n \u003cli\u003eSharma P, Stecklein SR, Yoder R, Staley JM, Schwensen K, O\u0026rsquo;Dea A, et al. Clinical and Biomarker Findings of Neoadjuvant Pembrolizumab and Carboplatin Plus Docetaxel in Triple-Negative Breast Cancer NeoPACT Phase 2 Clinical Trial. JAMA Oncol 2024. https://doi.org/10.1001/jamaoncol.2023.5033.\u003c/li\u003e\n \u003cli\u003ePusztai L, Denkert C, O\u0026rsquo;Shaughnessy J, Cortes J, Dent R, McArthur H, et al. Event-free survival by residual cancer burden with pembrolizumab in early-stage TNBC: exploratory analysis from KEYNOTE-522. Ann Oncol 2024;35:429\u0026ndash;36. https://doi.org/10.1016/j.annonc.2024.02.002.\u003c/li\u003e\n \u003cli\u003eMart\u0026iacute;n M, Yoder R, Salgado R, del Monte-Mill\u0026aacute;n M, \u0026Aacute;lvarez EL, Echavarr\u0026iacute;a I, et al. Tumor-Infiltrating Lymphocytes Refine Outcomes in Triple-Negative Breast Cancer Treated with Anthracycline-Free Neoadjuvant Chemotherapy. Clin Cancer Res 2024;30:2160\u0026ndash;9. https://doi.org/10.1158/1078-0432.CCR-24-0106.\u003c/li\u003e\n \u003cli\u003eLoi S, Drubay D, Adams S, Pruneri G, Francis PA, Lacroix-Triki M, et al. Tumor-infiltrating lymphocytes and prognosis: A pooled individual patient analysis of early-stage triple-negative breast cancers. J Clin Oncol 2019;37:559\u0026ndash;69. https://doi.org/10.1200/JCO.18.01010.\u003c/li\u003e\n \u003cli\u003eWood SJ, Gao Y, Lee JH, Chen J, Wang Q, Meisel JL, et al. High tumor infiltrating lymphocytes are significantly associated with pathological complete response in triple negative breast cancer treated with neoadjuvant KEYNOTE-522 chemoimmunotherapy. Breast Cancer Res Treat 2024;205:193\u0026ndash;9. https://doi.org/10.1007/s10549-023-07233-2.\u003c/li\u003e\n \u003cli\u003eLoi S, Michiels S, Adams S, Loibl S, Budczies J, Denkert C, et al. The journey of tumor-infiltrating lymphocytes as a biomarker in breast cancer: clinical utility in an era of checkpoint inhibition. Ann Oncol 2021. https://doi.org/10.1016/j.annonc.2021.07.007.\u003c/li\u003e\n \u003cli\u003eLoi S, Salgado R, Adams S, Pruneri G, Francis PA, Lacroix-Triki M, et al. Tumor infiltrating lymphocyte stratification of prognostic staging of early-stage triple negative breast cancer. Npj Breast Cancer 2022. https://doi.org/10.1038/s41523-021-00362-1.\u003c/li\u003e\n \u003cli\u003eSharma P, Siddiqui BA, Anandhan S, Yadav SS, Subudhi SK, Gao J, et al. The next decade of immune checkpoint therapy. Cancer Discov 2021. https://doi.org/10.1158/2159-8290.CD-20-1680.\u003c/li\u003e\n \u003cli\u003eMohamed RM, Panthi B, Adrada B, Candelaria R, Guirguis MS, Yang W, et al. Abstract P6-01-06: Multi-Parametric MRI-Based Radiomics Models from Tumor and Peritumoral Regions as Potential Predictors of Treatment Response to Neoadjuvant Systemic Therapy in Triple Negative Breast Cancer Patients. Cancer Res 2023. https://doi.org/10.1158/1538-7445.sabcs22-p6-01-06.\u003c/li\u003e\n \u003cli\u003eWang H, Yee D. I-SPY 2: a Neoadjuvant Adaptive Clinical Trial Designed to Improve Outcomes in High-Risk Breast Cancer. Curr Breast Cancer Rep 2019. https://doi.org/10.1007/s12609-019-00334-2.\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":"breast cancer, neoadjuvant treatment, immunotherapy","lastPublishedDoi":"10.21203/rs.3.rs-6734680/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6734680/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eTriple-negative breast cancer (TNBC) is a highly aggressive malignancy with limited therapeutic options and elevated mortality rates. Chemo-immunotherapy according to the KEYNOTE-522 has established a new standard of care in the neoadjuvant setting, due to high rates of pathological complete response (pCR) and improved survival outcomes. Considering the efficacy scenario, it is essential to explore whether and when treatment de-escalation may be feasible to mitigate toxicity. We report the clinical case of a 54-year-old Caucasian woman with high-risk cT4a cN0 TNBC who achieved both clinical and pathological complete response despite early discontinuation of neoadjuvant therapy. Due to anthracycline extravasation, four cycles of anthracyclines, cyclophosphamide, and pembrolizumab were omitted. This case suggests a potential role for de-escalated regimens in selected patients. However, the absence of reliable predictive biomarkers limits appropriate patient selection. Further investigation is warranted to identify which patients could safely benefit from reduced-intensity approaches without compromising outcomes.\u003c/p\u003e","manuscriptTitle":"Pathologic Complete Response in Triple Negative Breast Cancer Treated with Anthracycline Free Regimen: a case report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-14 11:16:09","doi":"10.21203/rs.3.rs-6734680/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 14th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-08-08T08:39:30+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-14 11:16:09","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6734680","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6734680","identity":"rs-6734680","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}