Special Issue "Treatment Strategies and Survival Outcomes in Breast Cancer"

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: 31 July 2019

Special Issue Editor

Guest Editor
Prof. Kwok-Leung Cheung

School of Medicine, University of Nottingham, Royal Derby Hospital Centre, DE22 3DT, UK
Website | E-Mail
Interests: Breast cancer; breast surgery; non-operative therapy; endocrine therapy; geriatric oncology

Special Issue Information

Dear Colleagues,

Treatment strategies for breast cancer are wide-ranging and often based on a multi-modality approach, depending on the stage and biology of the tumour and the acceptance and tolerance of the patient. They may include surgery, radiotherapy, and systemic therapy (endocrine therapy, chemotherapy, and targeted therapy). Advances in technologies such as oncoplastic surgery, radiation planning and delivery, and genomics, and the development of novel systemic therapy agents alongside their evaluation in ongoing clinical trials continue to strive for improvements in outcomes.

In this Special Issue, we welcome submissions looking at all forms of therapeutic strategies for early and advanced breast cancer, focusing on their outcomes, notably survival. It is desirable that the evaluation of survival outcomes be made against other outcome measures, such as toxicity, cost-effectiveness, and quality of life.

Prof. Kwok-Leung Cheung
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 papers will be 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 monthly 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 1800 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
  • early breast cancer
  • advanced breast cancer
  • surgery
  • radiotherapy
  • endocrine therapy
  • chemotherapy
  • targeted therapy
  • survival
  • toxicities
  • cost effectiveness
  • quality of life

Published Papers (7 papers)

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Research

Open AccessArticle Dasatinib Treatment Increases Sensitivity to c-Met Inhibition in Triple-Negative Breast Cancer Cells
Cancers 2019, 11(4), 548; https://doi.org/10.3390/cancers11040548 (registering DOI)
Received: 4 April 2019 / Accepted: 13 April 2019 / Published: 17 April 2019
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Abstract
In pre-clinical studies, triple-negative breast cancer (TNBC) cells have demonstrated sensitivity to the multi-targeted kinase inhibitor dasatinib; however, clinical trials with single-agent dasatinib showed limited efficacy in unselected populations of breast cancer, including TNBC. To study potential mechanisms of resistance to dasatinib in [...] Read more.
In pre-clinical studies, triple-negative breast cancer (TNBC) cells have demonstrated sensitivity to the multi-targeted kinase inhibitor dasatinib; however, clinical trials with single-agent dasatinib showed limited efficacy in unselected populations of breast cancer, including TNBC. To study potential mechanisms of resistance to dasatinib in TNBC, we established a cell line model of acquired dasatinib resistance (231-DasB). Following an approximately three-month exposure to incrementally increasing concentrations of dasatinib (200 nM to 500 nM) dasatinib, 231-DasB cells were resistant to the agent with a dasatinib IC50 value greater than 5 μM compared to 0.04 ± 0.001 µM in the parental MDA-MB-231 cells. 231-DasB cells also showed resistance (2.2-fold) to the Src kinase inhibitor PD180970. Treatment of 231-DasB cells with dasatinib did not inhibit phosphorylation of Src kinase. The 231-DasB cells also had significantly increased levels of p-Met compared to the parental MDA-MB-231 cells, as measured by luminex, and resistant cells demonstrated a significant increase in sensitivity to the c-Met inhibitor, CpdA, with an IC50 value of 1.4 ± 0.5 µM compared to an IC50 of 6.8 ± 0.2 µM in the parental MDA-MB-231 cells. Treatment with CpdA decreased p-Met and p-Src in both 231-DasB and MDA-MB-231 cells. Combined treatment with dasatinib and CpdA significantly inhibited the growth of MDA-MB-231 parental cells and prevented the emergence of dasatinib resistance. If these in vitro findings can be extrapolated to human cancer treatment, combined treatment with dasatinib and a c-Met inhibitor may block the development of acquired resistance and improve response rates to dasatinib treatment in TNBC. Full article
(This article belongs to the Special Issue Treatment Strategies and Survival Outcomes in Breast Cancer)
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Open AccessArticle Why Has Breast Cancer Screening Failed to Decrease the Incidence of de Novo Stage IV Disease?
Cancers 2019, 11(4), 500; https://doi.org/10.3390/cancers11040500
Received: 18 February 2019 / Revised: 31 March 2019 / Accepted: 3 April 2019 / Published: 8 April 2019
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Abstract
Background: Despite screening mammography, the incidence of Stage IV breast cancer (BC) at diagnosis has not decreased over the past four decades. We previously found that many BCs are small due to favorable biology rather than early detection. This study compared the [...] Read more.
Background: Despite screening mammography, the incidence of Stage IV breast cancer (BC) at diagnosis has not decreased over the past four decades. We previously found that many BCs are small due to favorable biology rather than early detection. This study compared the biology of Stage IV cancers with that of small cancers typically found by screening. Methods: Trends in the incidence of localized, regional, and distant female BC were compared using SEER*Stat. The National Cancer Database (NCDB) was then queried for invasive cancers from 2010 to 2015, and patient/disease variables were compared across stages. Biological variables including estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (Her2), grade, and lymphovascular invasion were sorted into 48 combinations, from which three biological subtypes emerged: indolent, intermediate, and aggressive. The distributions of the subtypes were compared across disease stages. Multivariable regression assessed the association between Stage IV disease and biology. Results: SEER*Stat confirmed that the incidence of distant BC increased between 1973 and 2015 (annual percent change [APC] = 0.46). NCDB data on roughly 993,000 individuals showed that Stage IV disease at presentation is more common in young, black, uninsured women with low income/education and large, biologically aggressive tumors. The distribution of tumor biology varied by stage, with Stage IV disease including 37.6% aggressive and 6.0% indolent tumors, versus sub-centimeter Stage I disease that included 5.1% aggressive and 40.6% indolent tumors (p < 0.001). The odds of Stage IV disease presentation more than tripled for patients with aggressive tumors (OR3.2, 95% CI 3.0–3.5). Conclusions: Stage I and Stage IV breast cancers represent very different populations of biologic tumor types. This may explain why the incidence of Stage IV cancer has not decreased with screening. Full article
(This article belongs to the Special Issue Treatment Strategies and Survival Outcomes in Breast Cancer)
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Open AccessArticle Impact of Overdiagnosis on Long-Term Breast Cancer Survival
Cancers 2019, 11(3), 325; https://doi.org/10.3390/cancers11030325
Received: 26 January 2019 / Revised: 24 February 2019 / Accepted: 4 March 2019 / Published: 7 March 2019
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Abstract
Elucidating whether and how long-term survival of breast cancer is mainly due to cure after early detection and effective treatment and therapy or overdiagnosis resulting from the widespread use of mammography provides a new insight into the role mammography plays in screening, surveillance, [...] Read more.
Elucidating whether and how long-term survival of breast cancer is mainly due to cure after early detection and effective treatment and therapy or overdiagnosis resulting from the widespread use of mammography provides a new insight into the role mammography plays in screening, surveillance, and treatment of breast cancer. Given information on detection modes, the impact of overdiagnosis due to mammography screening on long-term breast cancer survival was quantitatively assessed by applying a zero (cured or overdiagnosis)-inflated model design and analysis to a 15-year follow-up breast cancer cohort in Dalarna, Sweden. The probability for non-progressive breast cancer (the zero part) was 56.14% including the 44.34% complete cure after early detection and initial treatment and a small 11.80% overdiagnosis resulting from mammography screening program (8.94%) and high awareness (2.86%). The 15-year adjusted cumulative survival of breast cancer was dropped from 88.25% to 74.80% after correcting for the zero-inflated part of overdiagnosis. The present findings reveal that the majority of survivors among women diagnosed with breast cancer could be attributed to the cure resulting from mammography screening and accompanying effective treatment and therapy and only a small fraction of those were due to overdiagnosis. Full article
(This article belongs to the Special Issue Treatment Strategies and Survival Outcomes in Breast Cancer)
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Open AccessArticle Cell-Free DNA Variant Sequencing Using CTC-Depleted Blood for Comprehensive Liquid Biopsy Testing in Metastatic Breast Cancer
Cancers 2019, 11(2), 238; https://doi.org/10.3390/cancers11020238
Received: 21 January 2019 / Revised: 8 February 2019 / Accepted: 12 February 2019 / Published: 18 February 2019
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Abstract
Liquid biopsy analytes such as cell-free DNA (cfDNA) and circulating tumor cells (CTCs) exhibit great potential for personalized treatment. Since cfDNA and CTCs are considered to give additive information and blood specimens are limited, isolation of cfDNA and CTC in an “all from [...] Read more.
Liquid biopsy analytes such as cell-free DNA (cfDNA) and circulating tumor cells (CTCs) exhibit great potential for personalized treatment. Since cfDNA and CTCs are considered to give additive information and blood specimens are limited, isolation of cfDNA and CTC in an “all from one tube” format is desired. We investigated whether cfDNA variant sequencing from CTC-depleted blood (CTC-depl. B; obtained after positive immunomagnetic isolation of CTCs (AdnaTest EMT-2/Stem Cell Select, QIAGEN)) impacts the results compared to cfDNA variant sequencing from matched whole blood (WB). Cell-free DNA was isolated using matched WB and CTC-depl. B from 17 hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2−) metastatic breast cancer patients (QIAamp MinElute ccfDNA Kit, QIAGEN). Cell-free DNA libraries were constructed (customized QIAseq Targeted DNA Panel for Illumina, QIAGEN) with integrated unique molecular indices. Sequencing (on the NextSeq 550 platform, Illumina) and data analysis (Ingenuity Variant Analysis) were performed. RNA expression in CTCs was analyzed by multimarker quantitative PCR. Cell-free DNA concentration and size distribution in the matched plasma samples were not significantly different. Seventy percent of all variants were identical in matched WB and CTC-depl. B, but 115/125 variants were exclusively found in WB/CTC-depl. B. The number of detected variants per patient and the number of exclusively detected variants per patient in only one cfDNA source did not differ between the two matched cfDNA sources. Even the characteristics of the exclusively detected cfDNA variants in either WB or CTC-depl. B were comparable. Thus, cfDNA variants from matched WB and CTC-depl. B exhibited no relevant differences, and parallel isolation of cfDNA and CTCs from only 10 mL of blood in an “all from one tube” format was feasible. Matched cfDNA mutational and CTC transcriptional analyses might empower a comprehensive liquid biopsy analysis to enhance the identification of actionable targets for individual therapy strategies. Full article
(This article belongs to the Special Issue Treatment Strategies and Survival Outcomes in Breast Cancer)
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Open AccessArticle Mastectomy or Breast-Conserving Therapy for Early Breast Cancer in Real-Life Clinical Practice: Outcome Comparison of 7565 Cases
Cancers 2019, 11(2), 160; https://doi.org/10.3390/cancers11020160
Received: 27 December 2018 / Revised: 22 January 2019 / Accepted: 28 January 2019 / Published: 31 January 2019
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Abstract
Although the organ preservation strategy by breast-conserving surgery (BCS) followed by radiation therapy (BCT) has revolutionized the treatment approach of early stage breast cancer (BC), the choice between treatment options in this setting can still vary according to patient preferences. The aim of [...] Read more.
Although the organ preservation strategy by breast-conserving surgery (BCS) followed by radiation therapy (BCT) has revolutionized the treatment approach of early stage breast cancer (BC), the choice between treatment options in this setting can still vary according to patient preferences. The aim of the present study was to compare the oncological outcome of mastectomy versus breast-conserving therapy in patients treated in a modern clinical setting outside of clinical trials. 7565 women diagnosed with early invasive BC (pT1/2pN0/1) between 1998 and 2014 were included in this study (median follow-up: 95.2 months). In order to reduce selection bias and confounding, a subgroup analysis of a matched 1:1 case-control cohort consisting of 1802 patients was performed (median follow-up 109.4 months). After adjusting for age, tumor characteristics and therapies, multivariable analysis for local recurrence-free survival identified BCT as an independent predictor for improved local control (hazard ratio [HR]:1.517; 95%confidence interval:1.092–2.108, p = 0.013) as compared to mastectomy alone in the matched cohort. Ten-year cumulative incidence (CI) of lymph node recurrences was 2.0% following BCT, compared to 5.8% in patients receiving mastectomy (p < 0.001). Similarly, 10-year distant-metastasis-free survival (89.4% vs. 85.5%, p = 0.013) was impaired in patients undergoing mastectomy alone. This translated into improved survival in patients treated with BCT (10-year overall survival (OS) estimates 85.3% vs. 79.3%, p < 0.001), which was also significant on multivariable analysis (p = 0.011). In conclusion, the present study showed that patients treated with BCS followed by radiotherapy had an improved outcome compared to radical mastectomy alone. Specifically, local control, distant control, and overall survival were significantly better using the conservative approach. Thus, as a result of the present study, physicians should encourage patients to receive BCS with radiotherapy rather than mastectomy, whenever it is medically feasible and appropriate. Full article
(This article belongs to the Special Issue Treatment Strategies and Survival Outcomes in Breast Cancer)
Open AccessArticle Liver Kinase B1—A Potential Therapeutic Target in Hormone-Sensitive Breast Cancer in Older Women
Cancers 2019, 11(2), 149; https://doi.org/10.3390/cancers11020149
Received: 10 December 2018 / Revised: 16 January 2019 / Accepted: 19 January 2019 / Published: 28 January 2019
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Abstract
Background: The role of liver kinase B1 (LKB1), a serine/threonine kinase, has been described in the development of PeutzJagher’s syndrome, where a proportion (~45%) of patients have developed breast cancer in their lifetime. Cell line studies have linked LKB1 with oestrogen receptors [...] Read more.
Background: The role of liver kinase B1 (LKB1), a serine/threonine kinase, has been described in the development of PeutzJagher’s syndrome, where a proportion (~45%) of patients have developed breast cancer in their lifetime. Cell line studies have linked LKB1 with oestrogen receptors (ER) and with the Adenosine monophosphate-activated protein kinase (AMPK) pathway for energy metabolism. However, limited studies have investigated protein expression of LKB1 in tumour tissues and its intracellular relationships. This study aimed to investigate the intracellular molecular relationships of LKB1 in older women with early operable primary breast cancer and its correlation with long-term clinical outcome. Methods: Between 1973 and 2010, a consecutive series of 1758 older (≥70 years) women with T0-2N0-1M0 breast carcinoma were managed in a dedicated facility. Of these, 813 patients underwent primary surgery, and 575 had good quality tumour samples available for tissue microarray construction. LKB1 was assessed in 407 cases by indirect immunohistochemistry (IHC). Tumours with 30% or more of cells with cytoplasmic LKB1 expression were considered positive. LKB1 expression was compared with tumour size, histological grade, axillary lymph node stage, ER, PgR, EGFR, HER2, HER3, HER4, BRCA1&2, p53, Ki67, Bcl2, Muc1, E-Cadherin, CD44, basal (CK5, CK5/6, CK14 and CK17) and luminal (CK7/8, CK18 and CK19) cytokeratins, MDM2 and MDM4, and correlated with long-term clinical outcome. Results: Positive LKB1 expression was seen in 318 (78.1%) patients, and was significantly associated with high tumour grade, high Ki67, over-expression of HER2, VEGF, HER4, BRCA2, MDM2 and negative expression of CD44 (p < 0.05). There was no significant correlation with tumour size, axillary lymph node status, ER, PgR, p53, basal or luminal cytokeratins, Bcl2, Muc1, EGFR, HER3, MDM4, E-cadherin and BRCA1. LKB1 did not show any significant influence on survival in the overall population; however, in those patients receiving adjuvant endocrine therapy for ER positive tumours, those with positive LKB1 had significantly better 5-year breast cancer specific survival when compared to those without such expression (93% versus 74%, p = 0.03). Conclusion: LKB1 expression has shown association with poor prognostic factors in older women with breast cancer. However, LKB1 expression appears to be associated with better survival outcome among those patients receiving adjuvant endocrine therapy. Further research is required to explore its potential role as a therapeutic target. Full article
(This article belongs to the Special Issue Treatment Strategies and Survival Outcomes in Breast Cancer)
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Open AccessArticle Therapy Landscape in Patients with Metastatic HER2-Positive Breast Cancer: Data from the PRAEGNANT Real-World Breast Cancer Registry
Received: 28 October 2018 / Revised: 16 December 2018 / Accepted: 19 December 2018 / Published: 21 December 2018
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Abstract
This study presents comprehensive real-world data on the use of anti-human epidermal growth factor receptor 2 (HER2) therapies in patients with HER2-positive metastatic breast cancer (MBC). Specifically, it describes therapy patterns with trastuzumab (H), pertuzumab + trastuzumab (PH), lapatinib (L), and trastuzumab emtansine [...] Read more.
This study presents comprehensive real-world data on the use of anti-human epidermal growth factor receptor 2 (HER2) therapies in patients with HER2-positive metastatic breast cancer (MBC). Specifically, it describes therapy patterns with trastuzumab (H), pertuzumab + trastuzumab (PH), lapatinib (L), and trastuzumab emtansine (T-DM1). The PRAEGNANT study is a real-time, real-world registry for MBC patients. All therapy lines are documented. This analysis describes the utilization of anti-HER2 therapies as well as therapy sequences. Among 1936 patients in PRAEGNANT, 451 were HER2-positive (23.3%). In the analysis set (417 patients), 53% of whom were included in PRAEGNANT in the first-line setting, 241 were treated with H, 237 with PH, 85 with L, and 125 with T-DM1 during the course of their therapies. The sequence PH → T-DM1 was administered in 51 patients. Higher Eastern Cooperative Oncology Group (ECOG) scores, negative hormone receptor status, and visceral or brain metastases were associated with more frequent use of this therapy sequence. Most patients received T-DM1 after treatment with pertuzumab. Both novel therapies (PH and T-DM1) are utilized in a high proportion of HER2-positive breast cancer patients. As most patients receive T-DM1 after PH, real-world data may help to clarify whether the efficacy of this sequence is similar to that in the approval study. Full article
(This article belongs to the Special Issue Treatment Strategies and Survival Outcomes in Breast Cancer)
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