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Cancers
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Neoadjuvant Therapy of Breast Cancer
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Neoadjuvant Therapy of Breast Cancer

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: 15 June 2025 | Viewed by 14693

Special Issue Editors

Prof. Dr. Hiroyuki Takei

E-Mail Website
Guest Editor
Department of Breast Surgery and Oncology, Nippon Medical School, Bunkyo City, Tokyo 113-8602, Japan
Interests: breast cancer; endocrine therapy; chemotherapy; surgical therapy; tumor angiogenesis
Special Issues, Collections and Topics in MDPI journals
Dr. Takaaki Fujii

E-Mail Website
Guest Editor
Division of Breast and Endocrine Surgery, Graduate School of Medicine, Gunma University, Maebashi, Gunma, Japan
Interests: tumor-infiltrating lymphocytes; FDG-PETCT; immune checkpoint inhibitors; angiogenesis; predictive markers for response

Special Issue Information

Dear Colleagues,

Perioperative systemic therapy for operable breast cancer is subdivided according to the molecular subtype and clinical or pathologic stage. Molecular subtypes are alternatively classified into five pathologic subtypes based on immunohistochemical staining, such as luminal A, luminal B (HER2-negative), luminal B (HER2-positive), HER2-enriched, and triple-negative.

Perioperative treatment regimens are broadly categorized as endocrine therapy alone for luminal A tumors; endocrine therapy and chemotherapy for luminal B (HER2-negative) tumors; endocrine therapy, chemotherapy, molecular targeted therapy, and antibody drug conjugates (ADCs) for luminal B (HER2-positive) tumors; and chemotherapy, molecularly targeted therapy, and ADCs for HER2-enriched or triple-negative tumors. Molecularly targeted therapies include anti-HER2 antibodies and immune checkpoint inhibitors. The antibody drug conjugate is T-DM1. In addition to these treatment regimens, guidelines recommend the addition of CDK4/6 inhibitors, capecitabine, TS-1 (indicated in Japan only), and PARP inhibitors (in the presence of germline BRCA1/2 mutations) based on the degree of response to neoadjuvant therapy (e.g., the presence or absence of pCR).

In this highly segmented treatment regimen, it would be useful to consolidate and organize the discussion according to the five molecular subtypes mentioned above, focusing on the neoadjuvant setting followed by response-guided therapy. We believe that there is an important need for evidence-based review articles, real-world data articles including specific issues in actual clinical practice, and introductory articles on the latest clinical trials.

Prof. Dr. Hiroyuki Takei
Dr. Takaaki Fujii
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • neoadjuvant systemic therapy
  • chemotherapy
  • endocrine therapy
  • molecular targeted therapy
  • molecular subtypes
  • response-guided therapy
  • clinical trials

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Published Papers (8 papers)

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12 pages, 1208 KiB  
Article
Oncological Safety of Prepectoral Implant-Based Breast Reconstruction After Conservative Mastectomy: Insights from 842 Consecutive Breast Cancer Patients
by Lorenzo Scardina, Alba Di Leone, Alejandro Martin Sanchez, Cristina Accetta, Liliana Barone Adesi, Ersilia Biondi, Beatrice Carnassale, Sabatino D’Archi, Flavia De Lauretis, Enrico Di Guglielmo, Antonio Franco, Stefano Magno, Francesca Moschella, Maria Natale, Marzia Salgarello, Eleonora Savia, Marta Silenzi, Giuseppe Visconti, Riccardo Masetti and Gianluca Franceschini
Cancers 2025, 17(6), 925; https://doi.org/10.3390/cancers17060925 - 8 Mar 2025
Cited by 1 | Viewed by 732
Abstract
Background: Implant-based breast reconstruction (IBBR) following conservative mastectomy is the most common approach for women undergoing breast cancer surgery. The aim of this study was to compare the oncological outcomes of conservative mastectomy combined with prepectoral IBBR to the subpectoral technique. Methods: The [...] Read more.
Background: Implant-based breast reconstruction (IBBR) following conservative mastectomy is the most common approach for women undergoing breast cancer surgery. The aim of this study was to compare the oncological outcomes of conservative mastectomy combined with prepectoral IBBR to the subpectoral technique. Methods: The clinical and demographic data of consecutive breast cancer patients who underwent conservative mastectomy with either prepectoral or subpectoral IBBR between January 2018 and December 2023 were retrospectively analyzed. The primary outcome was the impact of conservative mastectomy with prepectoral IBBR on local recurrence-free survival (LRFS). Secondary outcomes included distant disease-free survival (DDFS) and overall survival (OS). Results: A total of 842 women (with a median age of 46 years and a range of 20–79 years) were included in the study. Of these, 648 patients (77.0%) underwent prepectoral IBBR, while 194 (23.0%) received subpectoral IBBR. The median follow-up was 32 months (3–74). Locoregional relapse occurred in 19 patients (2.9%) in the prepectoral group and 14 (7.2%) in the subpectoral group. Distant metastases were observed in 21 (3.2%) patients in the prepectoral group and 11 (5.7%) in the subpectoral group. Deaths were reported in eight patients (1.2%) in the prepectoral group and five (2.6%) in the subpectoral group. There were no statistically significant differences between the two groups in terms of the LRFS, DDFS, and OS (p = 0.676; p = 0.994; p = 0.940, respectively). Conclusions: Our study indicates that conservative mastectomy combined with prepectoral IBBR produces similar results to those of the subpectoral approach, with no significant differences in LRFS, DDFS, and OS. Full article
(This article belongs to the Special Issue Neoadjuvant Therapy of Breast Cancer)
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18 pages, 3344 KiB  
Article
Integrin α6β4 Upregulates PTPRZ1 Through UCHL1-Mediated Hif-1α Nuclear Accumulation to Promote Triple-Negative Breast Cancer Cell Invasive Properties
by Min Chen, Parvanee A. Karimpour, Andrew Elliott, Daheng He, Teresa Knifley, Jinpeng Liu, Chi Wang and Kathleen L. O’Connor
Cancers 2024, 16(21), 3683; https://doi.org/10.3390/cancers16213683 - 31 Oct 2024
Viewed by 1518
Abstract
Integrin α6β4 drives triple-negative breast cancer (TNBC) aggressiveness through the transcriptional regulation of key genes. Here, we investigated how integrin α6β4 regulates protein tyrosine phosphatase receptor type Z1 (PTPRZ1). Using stable re-expression of integrin β4 (ITGB4) in cells naturally devoid of integrin α6β4 [...] Read more.
Integrin α6β4 drives triple-negative breast cancer (TNBC) aggressiveness through the transcriptional regulation of key genes. Here, we investigated how integrin α6β4 regulates protein tyrosine phosphatase receptor type Z1 (PTPRZ1). Using stable re-expression of integrin β4 (ITGB4) in cells naturally devoid of integrin α6β4 or knockdown or knockout (KO) of ITGB4, we found that integrin α6β4 regulates PTPRZ1 expression. To gain mechanistic insight, we focused on Hif-1α due to the impact of integrin α6β4 on a hypoxia-associated signature. We found that nuclear localization of Hif-1α, but not Hif-2α, was substantially enhanced with integrin α6β4 signaling. Hif-1α knockdown by shRNA or chemical inhibition decreased PTPRZ1 expression, while chemical activation of Hif-1α increased it. Upstream of Hif-1α, integrin α6β4 upregulates UCHL1 to stabilize Hif-1α and ultimately regulate PTPRZ1. Inhibition of UCHL1 and PTPRZ1 dramatically decreases integrin α6β4-mediated cell migration and three-dimensional invasive growth. Finally, public breast cancer database analyses demonstrated that ITGB4 correlates with PTPRZ1 and that high expression of ITGB4, UCHL1, HIF1A, and PTPRZ1 associated with decreased overall survival, distant metastasis free survival, post progression survival, and relapse-free survival. In summary, these findings provide a novel function of integrin α6β4 in promoting tumor invasive phenotypes through UCHL1-Hif-1α-mediated regulation of PTPRZ1. Full article
(This article belongs to the Special Issue Neoadjuvant Therapy of Breast Cancer)
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16 pages, 1683 KiB  
Article
De-Escalation of Axillary Surgery in Clinically Node-Positive Breast Cancer Patients Treated with Neoadjuvant Therapy: Comparative Long-Term Outcomes of Sentinel Lymph Node Biopsy versus Axillary Lymph Node Dissection
by Corrado Tinterri, Erika Barbieri, Andrea Sagona, Simone Di Maria Grimaldi and Damiano Gentile
Cancers 2024, 16(18), 3168; https://doi.org/10.3390/cancers16183168 - 15 Sep 2024
Cited by 10 | Viewed by 2067
Abstract
Backgrounds: This study compares the long-term outcomes of axillary lymph node dissection (ALND) versus sentinel lymph node biopsy (SLNB) in clinically node-positive (cN+) breast cancer (BC) patients treated with neoadjuvant therapy (NAT).Methods: We conducted a retrospective analysis of 322 cN+ BC patients who [...] Read more.
Backgrounds: This study compares the long-term outcomes of axillary lymph node dissection (ALND) versus sentinel lymph node biopsy (SLNB) in clinically node-positive (cN+) breast cancer (BC) patients treated with neoadjuvant therapy (NAT).Methods: We conducted a retrospective analysis of 322 cN+ BC patients who became clinically node-negative (ycN0) post-NAT. Patients were categorized based on the final type of axillary surgery performed: ALND or SLNB. Recurrence-free survival (RFS), distant disease-free survival (DDFS), overall survival (OS), and breast cancer-specific survival (BCSS) were evaluated and compared between the two groups. Results: Patients in the SLNB group had significantly better 3-, 5-, and 10-year RFS, DDFS, OS, and BCSS compared to those in the ALND group. The SLNB group also had a higher proportion of patients achieving pathologic complete response (pCR). Multivariate analysis identified pCR, ypN0 status, and SLNB as favorable prognostic factors for all survival metrics. Axillary recurrence rates were low for both groups (0.6–2.1%). Conclusions: SLNB may be a safe and effective alternative to ALND for selected cN+ BC patients who convert to ycN0 after NAT. These findings suggest that careful patient selection is crucial, and further research is needed to validate these results in more comparable populations. Full article
(This article belongs to the Special Issue Neoadjuvant Therapy of Breast Cancer)
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25 pages, 4340 KiB  
Article
Evaluation of the Mammalian Aquaporin Inhibitors Auphen and Z433927330 in Treating Breast Cancer
by Verodia Charlestin, Elijah Tan, Carlos Eduardo Arias-Matus, Junmin Wu, Maria Cristina Miranda-Vergara, Mijoon Lee, Man Wang, Dharma T. Nannapaneni, Parinda Tennakoon, Brian S. J. Blagg, Brandon L. Ashfeld, William Kaliney, Jun Li and Laurie E. Littlepage
Cancers 2024, 16(15), 2714; https://doi.org/10.3390/cancers16152714 - 30 Jul 2024
Cited by 2 | Viewed by 1882
Abstract
AQPs contribute to breast cancer progression and metastasis. We previously found that genetic inhibition of Aqp7 reduces primary tumor burden and metastasis in breast cancer. In this study, we utilized two AQP inhibitors, Auphen and Z433927330, to evaluate the efficacy of therapeutic inhibition [...] Read more.
AQPs contribute to breast cancer progression and metastasis. We previously found that genetic inhibition of Aqp7 reduces primary tumor burden and metastasis in breast cancer. In this study, we utilized two AQP inhibitors, Auphen and Z433927330, to evaluate the efficacy of therapeutic inhibition of AQPs in breast cancer treatment. The inhibitors were evaluated in breast cancer for both cytotoxicity and metabolic stability assays across both murine and human breast cancer cell lines. Both AQP inhibitors also affected the expression of other AQP transcripts and proteins, which demonstrates compensatory regulation between AQP family members. As a single agent, Auphen treatment in vivo extended overall survival but did not impact primary or metastatic tumor burden. However, Auphen treatment made cells more responsive to chemotherapy (doxorubicin) or endocrine treatment (tamoxifen, fulvestrant). In fact, treatment with Tamoxifen reduced overall AQP7 protein expression. RNA-seq of breast cancer cells treated with Auphen identified mitochondrial metabolism genes as impacted by Auphen and may contribute to reducing mammary tumor progression, lung metastasis, and increased therapeutic efficacy of endocrine therapy in breast cancer. Interestingly, we found that Auphen and tamoxifen cooperate to reduce breast cancer cell viability, which suggests that Auphen treatment makes the cells more susceptible to Tamoxifen. Together, this study highlights AQPs as therapeutic vulnerabilities of breast cancer metastasis that are promising and should be exploited. However, the pharmacologic results suggest additional chemical refinements and optimization of AQP inhibition are needed to make these AQP inhibitors appropriate to use for therapeutic benefit in overcoming endocrine therapy resistance. Full article
(This article belongs to the Special Issue Neoadjuvant Therapy of Breast Cancer)
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15 pages, 4042 KiB  
Article
Targeting the Cell Cycle, RRM2 and NF-κB for the Treatment of Breast Cancers
by Nahid Sultana, Howard L. Elford and Jesika S. Faridi
Cancers 2024, 16(5), 975; https://doi.org/10.3390/cancers16050975 - 28 Feb 2024
Cited by 1 | Viewed by 2355
Abstract
A hallmark of cancer is the dysregulation of the cell cycle. The CDK4/6 inhibitor palbociclib is approved for treating advanced estrogen-receptor-positive breast cancer, but its success is limited by the development of acquired resistance owing to long-term therapy despite promising clinical outcomes. This [...] Read more.
A hallmark of cancer is the dysregulation of the cell cycle. The CDK4/6 inhibitor palbociclib is approved for treating advanced estrogen-receptor-positive breast cancer, but its success is limited by the development of acquired resistance owing to long-term therapy despite promising clinical outcomes. This situation necessitates the development of potential combination strategies. Here, we report that didox, an inhibitor of ribonucleotide reductase in combination with palbociclib, can overcome palbociclib resistance in ER-positive and ER-negative breast cancers. This study shows didox downregulates an element of the cell cycle checkpoint, cyclin D1, accompanied by a reduction in NF-κB activity in vitro and tumor growth inhibition of palbociclib-resistant ER positive breast cancer tumor growth in vivo. Furthermore, didox induces cell cycle arrest at G1 as well as reduces ROS generated by on-target effects of palbociclib on the cell cycle. Our current study also reports that the CCND1 and RRM2 upregulation associated with palbociclib-resistant breast cancers decreases upon ribonucleotide reductase inhibition. Our data present a novel and promising biomarker-driven combination therapeutic approach for the treatment of ER-positive and ER-negative breast cancers that involves the inhibition of the CDK4/6-cyclinD1/pRb cell cycle axis that merits further clinical investigation in human models. Full article
(This article belongs to the Special Issue Neoadjuvant Therapy of Breast Cancer)
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14 pages, 1878 KiB  
Article
Predictive Markers of Treatment Response to Neoadjuvant Systemic Therapy with Dual HER2-Blockade
by Soong June Bae, Jee Hung Kim, Min Ji Lee, Seung Ho Baek, Yoonwon Kook, Sung Gwe Ahn, Yoon Jin Cha and Joon Jeong
Cancers 2024, 16(4), 842; https://doi.org/10.3390/cancers16040842 - 19 Feb 2024
Cited by 3 | Viewed by 1893
Abstract
In patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer, achievement of pathologic complete response (pCR) is a known prognostic indicator after neoadjuvant systemic therapy (NAST). We investigated the clinicopathological factors associated with pCR in patients with HER2-positive breast cancer treated [...] Read more.
In patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer, achievement of pathologic complete response (pCR) is a known prognostic indicator after neoadjuvant systemic therapy (NAST). We investigated the clinicopathological factors associated with pCR in patients with HER2-positive breast cancer treated with dual HER2-blockade. In this retrospective study, 348 patients with HER2-positive breast cancer who received NAST with docetaxel and carboplatin, combined with trastuzumab and pertuzumab (TCHP), were included. Of the 348 patients with HER2 protein expression data, 278 (79.9%) had HER2 immunochemistry (IHC) 3+. Data on tumor-infiltrating lymphocyte (TIL) levels were available for 305 patients, showing a median TIL level of 20% (IQR 5–50), among which 121 (39.7%) had high TIL levels (≥30%). Estrogen receptor (ER) status (77.9% in ER-negative vs. 47.5% in ER-positive; p < 0.001), HER2 protein expression (71.6% in IHC 3+ vs. 34.3% in IHC 2+; p < 0.001), and TIL levels (71.9% in high vs. 57.6% in low; p = 0.011) were significantly associated with the pCR rate. In addition, we observed a significant link between numerical TIL levels (per 10% increment) and the pCR rate. After adjusting other clinicopathologic factors, ER status (low expression [defined as 1–9% expression] or negative), HER2 IHC 3+ and numerical TIL levels (per 10% increment), and high TIL levels (≥30%) were found to be independent predictors of pCR. Notably, in ER-negative breast cancer, the treatment response was excellent, irrespective of HER2 expression and TIL levels. Conversely, in ER-positive cases, low ER expression, HER2 IHC 3+, and numerical TIL levels or high TIL levels emerged as independent predictors of pCR. Our results suggest that ER expression, HER2 protein expression, and TIL levels serve as valuable predictors of the treatment response to neoadjuvant TCHP. Full article
(This article belongs to the Special Issue Neoadjuvant Therapy of Breast Cancer)
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13 pages, 922 KiB  
Article
The Impact of Different Patterns of Residual Disease on Long-Term Oncological Outcomes in Breast Cancer Patients Treated with Neo-Adjuvant Chemotherapy
by Corrado Tinterri, Bethania Fernandes, Alberto Zambelli, Andrea Sagona, Erika Barbieri, Simone Di Maria Grimaldi, Shadya Sara Darwish, Flavia Jacobs, Camilla De Carlo, Martina Iuzzolino and Damiano Gentile
Cancers 2024, 16(2), 376; https://doi.org/10.3390/cancers16020376 - 16 Jan 2024
Cited by 14 | Viewed by 2158
Abstract
Backgrounds: The majority of breast cancer (BC) patients treated with neo-adjuvant chemotherapy (NAC) achieves a pathologic partial response with different patterns of residual disease. No clear correlation between these patterns and oncological results was described. Our aims were to define the predictive factors [...] Read more.
Backgrounds: The majority of breast cancer (BC) patients treated with neo-adjuvant chemotherapy (NAC) achieves a pathologic partial response with different patterns of residual disease. No clear correlation between these patterns and oncological results was described. Our aims were to define the predictive factors for different patterns of residual disease and compare the outcomes between the scattered versus the circumscribed pattern. Methods: We reviewed 219 postoperative surgical specimens. Patients were divided into two groups: scattered versus circumscribed. Disease-free survival (DFS), distant DFS (DDFS), and overall survival (OS) were analyzed. Results: The scattered and circumscribed patterns were assessed in 111 (50.7%) and 108 (49.3%) patients. Two independent predictive factors for the circumscribed pattern were identified: discontinuation of NAC cycles (p = 0.011), and tumor size post-NAC >18 mm (p = 0.022). No difference was observed in terms of DFS and DDFS. Patients with the scattered pattern exhibited a statistically significant better OS. Discontinuation of NAC cycles, tumor size >18 mm, triple-negative BC, and ypN+ were associated with increased recurrence and poorer survival. Conclusions: Discontinuation of NAC cycles and tumor size are independent factors associated with patterns of residual disease. The scattered pattern presents better survival. Understanding the relationship between NAC, the residual pattern, and differences in survival outcomes offers the potential to optimize the therapeutic approaches. Full article
(This article belongs to the Special Issue Neoadjuvant Therapy of Breast Cancer)
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13 pages, 274 KiB  
Study Protocol
Dose-Limiting Toxicities of Paclitaxel in Breast Cancer Patients: Studying Interactions Between Pharmacokinetics, Physical Activity, and Body Composition—A Protocol for an Observational Cohort Study
by Len De Nys, Anita Barzegar-Fallah, Katrien Lanckmans, Stephane Steurbaut, David Beckwée, Amy de Haar-Holleman, Steven Provyn, Elke Gasthuys, Sofie Vande Casteele, Pieter-Jan De Sutter, An Vermeulen, Jan Van Bocxlaer, Stephanie C. M. Wuyts and Nele Adriaenssens
Cancers 2025, 17(1), 50; https://doi.org/10.3390/cancers17010050 - 27 Dec 2024
Cited by 1 | Viewed by 1329
Abstract
Background/Objectives: Paclitaxel (PTX), a commonly used chemotherapy for breast cancer (BC), is associated with dose-limiting toxicities (DLTs) such as peripheral neuropathy and neutropenia. These toxicities frequently lead to dose reductions, treatment delays, or therapy discontinuation, negatively affecting patients’ quality of life and [...] Read more.
Background/Objectives: Paclitaxel (PTX), a commonly used chemotherapy for breast cancer (BC), is associated with dose-limiting toxicities (DLTs) such as peripheral neuropathy and neutropenia. These toxicities frequently lead to dose reductions, treatment delays, or therapy discontinuation, negatively affecting patients’ quality of life and clinical outcomes. Current dosing strategies based on body surface area (BSA) fail to account for individual variations in body composition (skeletal muscle mass (SMM) and adipose tissue (AT) mass) and physical activity (PA), which can influence drug metabolism and toxicity. This study aims to explore the relationships between PTX pharmacokinetics, body composition, and PA to predict DLTs. Methods: This single-group observational cohort study will recruit 40 female BC patients undergoing PTX treatment. Data collection will include plasma PTX concentrations, body composition assessments (using dual X-ray absorptiometry and bioelectrical impedance analysis), PA measurements (via accelerometers), and questionnaires to assess BC-related health-related quality of life, chemotherapy-induced peripheral neuropathy, and neutropenia during the PTX schedule using validated questionnaires. Dose-limiting toxicities will be graded according to the Common Terminology Criteria for Adverse Events v5.0 (grade 3 or higher). This protocol is designed to develop a population-based PK-PD model that predicts the occurrence of chemotherapy-induced peripheral neuropathy and neutropenia in women with stage II or III BC undergoing PTX therapy, focusing on explanatory outcomes related to SMM, AT mass, and PA. Full article
(This article belongs to the Special Issue Neoadjuvant Therapy of Breast Cancer)
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