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Cancers
Special Issues
Neoadjuvant Therapy in Breast Cancer
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Neoadjuvant Therapy in Breast Cancer

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

Deadline for manuscript submissions: closed (31 October 2021) | Viewed by 26123

Special Issue Editor

Dr. Theodoros Foukakis

E-Mail Website
Guest Editor
Department of Oncology-Pathology, Karolinska Institutet, 17164 Stockholm, Sweden
Interests: breast cancer; genomics; tumor microenvironment; predictive biomarkers; neoadjuvant therapy

Special Issue Information

Neoadjuvant therapy in breast cancer has recently expanded beyond its traditional indication of downstaging to make breast-conserving surgery possible. Large patient level meta-analyses show that neoadjuvant chemotherapy has equivalent efficacy compared with adjuvant therapy and that pathologic complete response (pCR) in the surgical specimen correlates with long-term outcomes. The association between pCR and survival is particularly apparent for the HER2-positive and triple-negative subtypes and more recent data show that following failure to achieve pCR, further adjuvant therapy significantly improves prognosis in these subtypes.

In addition to the demonstrated clinical value, neoadjuvant therapy has emerged as a platform for studying the biology of breast cancer and the dynamic evolution of both the tumor (e.g., by genomics) and the host response (tumor microenvironment) under the selection pressure of therapy. Furthermore, clinical trials of neoadjuvant therapy have used pCR as an endpoint for the rapid assessment of the efficacy of novel drugs before proceeding with large phase 3 trials.

However, several questions remain unanswered. High-throughput multi-omics methods and deep-learning approaches have the potential to further dissect the complexity of the disease, exploiting the opportunity provided by neoadjuvant therapy to study the tumor in situ during the course of treatment. Therapeutic algorithms, including the agents to be used, the duration of treatment, the incorporation of novel drugs and the optimization of local treatment (surgery, radiotherapy), vary between different countries and no universal standards of care exist. Prognostication after neoadjuvant treatment is mainly based on the presence or not of residual disease at surgery, which is suboptimal, especially for luminal tumors. This Special Issue will highlight the current state-of-the-art in neoadjuvant treatment and future prospects for improving our understanding of the biology and optimizing patient care.

Dr. Theodoros Foukakis
Guest Editor

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 short 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

  • breast cancer
  • neoadjuvant treatment
  • residual disease
  • tumor microenvironment
  • prognosis
  • chemotherapy
  • immunotherapy
  • tumor heterogeneity
  • genomics
  • gene expression

Published Papers (8 papers)

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Research

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16 pages, 2779 KiB  
Article
Are Mutation Carrier Patients Different from Non-Carrier Patients? Genetic, Pathology, and US Features of Patients with Breast Cancer
by Roxana Maria Pintican, Angelica Chiorean, Magdalena Duma, Diana Feier, Madalina Szep, Dan Eniu, Iulian Goidescu and Sorin Dudea
Cancers 2022, 14(11), 2759; https://doi.org/10.3390/cancers14112759 - 2 Jun 2022
Cited by 5 | Viewed by 1719
Abstract
The purpose of this study is to evaluate the relationship between the pathogenic/likely pathogenic mutations, US features, and histopathologic findings of breast cancer in mutation carriers compared to non-carrier patients. Methods: In this retrospective study, we identified 264 patients with breast cancer and [...] Read more.
The purpose of this study is to evaluate the relationship between the pathogenic/likely pathogenic mutations, US features, and histopathologic findings of breast cancer in mutation carriers compared to non-carrier patients. Methods: In this retrospective study, we identified 264 patients with breast cancer and multigene panel testing admitted to our clinic from January 2018 to December 2020. Patient data US findings, US assessment of the axilla, multigene panel tests, histopathology, and immunochemistry reports were reviewed according to the BI-RADS lexicon. Results: The study population was comprised of 40% pathogenic mutation carriers (BRCA1, BRCA2, CHEK2, ATM, PALB, TP 53, NBN, MSH, BRIP 1 genes) and 60% mutation-negative patients. The mean patient age was 43.5 years in the carrier group and 44 years in the negative group. Carrier patients developed breast cancer with benign morphology (acoustic enhancement, soft elastography appearance) compared to non-carriers (p < 0.05). A tendency towards specific US features was observed for each mutation. BRCA1 carriers were associated with BC with microlobulated margins, hyperechoic rim, and soft elastography appearance (p < 0.05). Estrogen receptor (ER)-negative tumors were associated with BRCA1, TP53, and RAD mutations, while BRCA2 and CHEK2 were associated with ER-positive tumors. Conclusions: Patients with pathogenic mutations may exhibit BC with benign US features compared to negative, non-carrier patients. BRCA1, TP53, and RAD carriers account for up to one third of the ER tumors from the carrier group. Axillary US performed worse in depicting involved lymph nodes in carrier patients, compared to negative patients. Full article
(This article belongs to the Special Issue Neoadjuvant Therapy in Breast Cancer)
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20 pages, 1852 KiB  
Article
Dynamics of Serum Thymidine Kinase 1 at the First Cycle of Neoadjuvant Chemotherapy Predicts Outcome of Disease in Estrogen-Receptor-Positive Breast Cancer
by Bernhard Tribukait
Cancers 2021, 13(21), 5442; https://doi.org/10.3390/cancers13215442 - 29 Oct 2021
Cited by 1 | Viewed by 2731
Abstract
Pathologic complete response (pCR) predicts the long-term outcome of neoadjuvantly treated (NAC) breast cancer (BC) but is reached in <10% of hormone-receptor-positive patients. Biomarkers enabling adjustment or interruption of an ineffective therapy are desired. Here, we evaluated whether changes in the serum concentration [...] Read more.
Pathologic complete response (pCR) predicts the long-term outcome of neoadjuvantly treated (NAC) breast cancer (BC) but is reached in <10% of hormone-receptor-positive patients. Biomarkers enabling adjustment or interruption of an ineffective therapy are desired. Here, we evaluated whether changes in the serum concentration of thymidine kinase 1 (sTK1) during NAC could be utilized as a biomarker. In the PROMIX trial, women with localized HER2- BC received neoadjuvant epirubicin/docetaxel in six cycles. sTK1 was measured with an ELISA in 54 patients at cycles 1–4 and in an additional 77 patients before and 48 h after treatment 1. Treatment resulted in a 2-fold increase of sTK1 before and a 3-fold increase 48 h after the cycles, except for the first cycle, where half of the patients reacted with a significant decrease and the other half with an increase of sTK1. In Kaplan–Meier estimates of ER+ patients divided by the median of the post/pre-treatment sTK1 ratio at the first treatment cycle, OS was 97.7% and 78% (p = 0.005), and DFS was 90.7% and 68% (p = 0.006), respectively. Thus, the response of sTK1 at the first cycle of chemotherapy could be used both as an early biomarker for the guidance of chemotherapy and for the study of inherent tumor chemo-sensitivity, which could predict long-term outcome prior to therapy. Full article
(This article belongs to the Special Issue Neoadjuvant Therapy in Breast Cancer)
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13 pages, 634 KiB  
Article
A Novel Immunomodulatory 27-Gene Signature to Predict Response to Neoadjuvant Immunochemotherapy for Primary Triple-Negative Breast Cancer
by Toshiaki Iwase, Kim R. M. Blenman, Xiaotong Li, Emily Reisenbichler, Robert Seitz, David Hout, Tyler J. Nielsen, Brock L. Schweitzer, Daniel B. Bailey, Yichao Shen, Xiang Zhang, Lajos Pusztai and Naoto T. Ueno
Cancers 2021, 13(19), 4839; https://doi.org/10.3390/cancers13194839 - 28 Sep 2021
Cited by 17 | Viewed by 5585
Abstract
A precise predictive biomarker for TNBC response to immunochemotherapy is urgently needed. We previously established a 27-gene IO signature for TNBC derived from a previously established 101-gene model for classifying TNBC. Here we report a pilot study to assess the performance of a [...] Read more.
A precise predictive biomarker for TNBC response to immunochemotherapy is urgently needed. We previously established a 27-gene IO signature for TNBC derived from a previously established 101-gene model for classifying TNBC. Here we report a pilot study to assess the performance of a 27-gene IO signature in predicting the pCR of TNBC to preoperative immunochemotherapy. We obtained RNA sequencing data from the primary tumors of 55 patients with TNBC, who received neoadjuvant immunochemotherapy with the PD-L1 blocker durvalumab. We determined the power and accuracy in predicting pCR for the immunomodulatory (IM) subtype identified by the 101-gene model, the 27-gene IO signature, and PD-L1 expression by immunohistochemistry (IHC). The pCR rate was 45% (25/55). The odds ratios for pCR were as follows: IM subtype by 101-gene model, 3.14 (p = 0.054); 27-gene IO signature, 4.13 (p = 0.012); PD-L1 expression by IHC, 2.63 (p = 0.106); 27-gene IO signature in combination with PD-L1 expression by IHC, 6.53 (p = 0.003). The 27-gene IO signature has the potential to predict the pCR of primary TNBC to neoadjuvant immunochemotherapy. Further analysis in a large cohort is needed. Full article
(This article belongs to the Special Issue Neoadjuvant Therapy in Breast Cancer)
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14 pages, 582 KiB  
Article
Hypnosis Sedation Reduces the Duration of Different Side Effects of Cancer Treatments in Breast Cancer Patients Receiving Neoadjuvant Chemotherapy
by Martine Berliere, Nathan Piette, Marion Bernard, Camille Lacroix, Amandine Gerday, Vasiliki Samartzi, Maude Coyette, Fabienne Roelants, Marie-Agnes Docquier, Nassim Touil, Christine Watremez, Philippe Piette and Fran×ois P. Duhoux
Cancers 2021, 13(16), 4147; https://doi.org/10.3390/cancers13164147 - 18 Aug 2021
Cited by 6 | Viewed by 3168
Abstract
Background: Reducing side effects of cancer treatments is a major challenge for clinicians involved in the management of breast cancer patients. Methods: We analyzed data from 63 patients (32 in the general anesthesia group and 31 in the hypnosis sedation group) who were [...] Read more.
Background: Reducing side effects of cancer treatments is a major challenge for clinicians involved in the management of breast cancer patients. Methods: We analyzed data from 63 patients (32 in the general anesthesia group and 31 in the hypnosis sedation group) who were included in 1 prospective non-randomized trial evaluating hypnosis sedation in breast cancer treatment. The patients were followed every 3 months for 2 years. All patients received neoadjuvant chemotherapy with 4 cycles of epirubicin and cyclophosphamide followed by taxanes. Thereafter, patients underwent surgery while on general anesthesia or while on hypnosis sedation. Radiotherapy was administered according to institutional guidelines. Endocrine therapy was prescribed if tumors expressed hormone receptors. Prevalence, intensity and duration of polyneuropathy, musculoskeletal pain, postoperative pain and cancer-related fatigue were assessed at each medical visit. Results: Symptoms duration was statistically reduced for polyneuropathy (p < 0.05), musculoskeletal pain (p < 0.05) postoperative pain and cancer-related fatigue (p < 0.05) in the hypnosis group. Conclusion: Despite the limitations of this study (lack of randomization and small size) we conclude that hypnosis sedation may exert a role on different side effects of breast cancer treatment in patients receiving neoadjuvant chemotherapy, mainly by reducing their duration. Full article
(This article belongs to the Special Issue Neoadjuvant Therapy in Breast Cancer)
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15 pages, 1867 KiB  
Article
A Novel Three-Gene Score as a Predictive Biomarker for Pathologically Complete Response after Neoadjuvant Chemotherapy in Triple-Negative Breast Cancer
by Masanori Oshi, Fernando A. Angarita, Yoshihisa Tokumaru, Li Yan, Ryusei Matsuyama, Itaru Endo and Kazuaki Takabe
Cancers 2021, 13(10), 2401; https://doi.org/10.3390/cancers13102401 - 16 May 2021
Cited by 16 | Viewed by 2738
Abstract
Although triple-negative breast cancer (TNBC) typically responds better to neoadjuvant chemotherapy (NAC) compared to the other subtypes, a pathological complete response (pCR) is achieved in less than half of the cases. We established a novel three-gene score using genes based on the E2F [...] Read more.
Although triple-negative breast cancer (TNBC) typically responds better to neoadjuvant chemotherapy (NAC) compared to the other subtypes, a pathological complete response (pCR) is achieved in less than half of the cases. We established a novel three-gene score using genes based on the E2F target gene set that identified pCR after NAC, which showed robust performance in both training and validation cohorts (total of n = 3862 breast cancer patients). We found that the three-gene score was elevated in TNBC compared to the other subtypes. A high score was associated with Nottingham histological grade 3 in TNBC. Across multiple cohorts, high-score TNBC enriched not only E2F targets but also G2M checkpoint and mitotic spindle, which are all cell proliferation-related gene sets. High-score TNBC was associated with homologous recombination deficiency, high mutation load, and high infiltration of Th1, Th2, and gamma-delta T cells. However, the score did not correlate with drug sensitivity for paclitaxel, 5-fluorouracil, cyclophosphamide, and doxorubicin in TNBC human cell lines. High-score TNBC was significantly associated with a high rate of pCR not only in the training cohort but also in the validation cohorts. High-score TNBC was significantly associated with better survival in patients who received chemotherapy but not in patients who did not receive chemotherapy. The three-gene score is associated with a high mutation rate, immune cell infiltration, and predicts response to NAC in TNBC. Full article
(This article belongs to the Special Issue Neoadjuvant Therapy in Breast Cancer)
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Review

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26 pages, 332 KiB  
Review
The Present and Future of Neoadjuvant Endocrine Therapy for Breast Cancer Treatment
by Covadonga Martí and José Ignacio Sánchez-Méndez
Cancers 2021, 13(11), 2538; https://doi.org/10.3390/cancers13112538 - 21 May 2021
Cited by 12 | Viewed by 3111
Abstract
Endocrine therapy (ET) has established itself as an efficacious treatment for estrogen receptor-positive (ER+) breast cancers, with a reduction in recurrence rates and increased survival rates. The pre-surgical approach with chemotherapy (NCT) has become a common form of management for large, locally advanced, [...] Read more.
Endocrine therapy (ET) has established itself as an efficacious treatment for estrogen receptor-positive (ER+) breast cancers, with a reduction in recurrence rates and increased survival rates. The pre-surgical approach with chemotherapy (NCT) has become a common form of management for large, locally advanced, or high-risk tumors. However, a good response to NCT is not usually expected in ER+ tumors. Good results with primary ET, mainly in elderly women, have encouraged studies in other stages of life, and nowadays neoadjuvant endocrine treatment (NET) has become a useful approach to many ER+ breast cancers. The aim of this review is to provide an update on the current state of art regarding the present and the future role of NET. Full article
(This article belongs to the Special Issue Neoadjuvant Therapy in Breast Cancer)

Other

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21 pages, 1389 KiB  
Systematic Review
Neoadjuvant Treatment with HER2-Targeted Therapies in HER2-Positive Breast Cancer: A Systematic Review and Network Meta-Analysis
by Agampodi Danushi M. Gunasekara, Thunyarat Anothaisintawee, Sitaporn Youngkong, Nguyen T. Ha, Gareth J. McKay, John Attia and Ammarin Thakkinstian
Cancers 2022, 14(3), 523; https://doi.org/10.3390/cancers14030523 - 21 Jan 2022
Cited by 4 | Viewed by 3387
Abstract
This systematic review aimed to identify neoadjuvant anti-human epidermal growth factor receptor 2 (HER2) therapies with the best balance between efficacy and safety. Methods: A network meta-analysis was applied to estimate the risk ratios along with 95% confidence intervals (CIs) for pathological complete [...] Read more.
This systematic review aimed to identify neoadjuvant anti-human epidermal growth factor receptor 2 (HER2) therapies with the best balance between efficacy and safety. Methods: A network meta-analysis was applied to estimate the risk ratios along with 95% confidence intervals (CIs) for pathological complete response (pCR) and serious adverse events (SAE). A mixed-effect parametric survival analysis was conducted to assess the disease-free survival (DFS) between treatments. Results: Twenty-one RCTs with eleven regimens of neoadjuvant anti-HER2 therapy (i.e., trastuzumab + chemotherapy (TC), lapatinib + chemotherapy (LC), pertuzumab + chemotherapy (PC), pertuzumab + trastuzumab (PT), trastuzumab emtansine + pertuzumab (T-DM1P), pertuzumab + trastuzumab + chemotherapy (PTC), lapatinib + trastuzumab + chemotherapy (LTC), trastuzumab emtansine + lapatinib + chemotherapy (T-DM1LC), trastuzumab emtansine + pertuzumab + chemotherapy(T-DM1PC), PTC followed by T-DM1P (PTC_T-DM1P), and trastuzumab emtansine (T-DM1)) and chemotherapy alone were included. When compared to TC, only PTC had a significantly higher DFS with a hazard ratio (95% CI) of 0.54 (0.32–0.91). The surface under the cumulative ranking curve (SUCRA) suggested that T-DM1LC (91.9%) was ranked first in achieving pCR, followed by the PTC_T-DM1P (90.5%), PTC (74.8%), and T-DM1PC (73.5%) regimens. For SAEs, LTC, LC, and T-DM1LC presented with the highest risks (SUCRA = 10.7%, 16.8%, and 20.8%), while PT (99.2%), T-DM1P (88%), and T-DM1 (83.9%) were the safest regimens. The T-DM1PC (73.5% vs. 71.6%), T-DM1 (70.5% vs. 83.9%), and PTC_T-DM1P (90.5% vs. 47.3%) regimens offered the optimal balance between pCR and SAE. Conclusions: The T-DM1PC, T-DM1, and PTC_T-DM1P regimens had the optimal balance between efficacy and safety, while DFS was highest for the PTC regimen. However, these results were based on a small number of studies, and additional RCTs assessing the efficacy of regimens with T-DM1 are still needed to confirm these findings. Full article
(This article belongs to the Special Issue Neoadjuvant Therapy in Breast Cancer)
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13 pages, 323 KiB  
Commentary
Circulating and Intracellular miRNAs as Prognostic and Predictive Factors in HER2-Positive Early Breast Cancer Treated with Neoadjuvant Chemotherapy: A Review of the Literature
by Chrystel Isca, Federico Piacentini, Ilenia Mastrolia, Valentina Masciale, Federica Caggia, Angela Toss, Claudia Piombino, Luca Moscetti, Monica Barbolini, Michela Maur, Massimo Dominici and Claudia Omarini
Cancers 2021, 13(19), 4894; https://doi.org/10.3390/cancers13194894 - 29 Sep 2021
Cited by 6 | Viewed by 2304
Abstract
MicroRNAs (miRNA) are small noncoding RNAs that can act as both oncogene and tumor suppressors. Deregulated miRNA expression has been detected in human cancers, including breast cancer (BC). Considering their important roles in tumorigenesis, miRNAs have been investigated as potential prognostic and diagnostic [...] Read more.
MicroRNAs (miRNA) are small noncoding RNAs that can act as both oncogene and tumor suppressors. Deregulated miRNA expression has been detected in human cancers, including breast cancer (BC). Considering their important roles in tumorigenesis, miRNAs have been investigated as potential prognostic and diagnostic biomarkers. Neoadjuvant setting is an optimal model to investigate in vivo the mechanism of treatment resistance. In the management of human epidermal growth factor receptor-2 (HER2)-positive early BC, the anti-HER2-targeted therapies have drastically changed the survival outcomes. Despite this, growing drug resistance due to the pressure of therapy is relatively frequent. In the present review, we focused on the main miRNAs involved in HER2-positive BC tumorigenesis and discussed the recent evidence on their predictive and prognostic value. Full article
(This article belongs to the Special Issue Neoadjuvant Therapy in Breast Cancer)
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