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Prognostic Factors Research in Breast Cancer Patients

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

Deadline for manuscript submissions: closed (1 August 2021) | Viewed by 34423

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Dr. Tommaso Susini

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Breast Unit, Gynecology Section, Department of Health Sciences, University of Florence, Florence, Italy
Interests: breast cancer treatment; prognostic factors; sentinel lymph node; individualized treatment; ovarian cancer; endometrial cancer
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Nicoletta Biglia

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Guest Editor

Academic Division of Obstetrics and Gynecology, Mauriziano Umberto 1st Hospital – School of Medicine, University of Torino, 10128 Torino, Italy
Interests: gynaecological and breast oncology; risk factors; predictive and prognostic factors; treatment of the primary disease; quality of life and reproductive issues after cancer

Special Issue Information

Dear Colleagues,

Breast cancer is the leading cause of cancer death worldwide, and its frequency is increasing at all ages. In the last few decades, there have been significant advancements in the diagnosis and treatment of breast cancer. However, many of these improvements imply the use of sophisticated techniques and expensive drugs not always available in every country. In particular, the clue to the innovation in breast cancer treatment was the identification of new prognostic factors, which we can search for in different molecular and immunohistochemical subtypes. They may be prognostic, predictive, or both and help in selecting the best treatment for each patient and in ruling out ineffective and high-risk treatments. As the research is continuously expanding in the field of prognostic factors for breast cancer patients, the aim of this Special Issue is to focus on the more recent advances in this field, with special reference to studies that have developed new approaches to individualize prognosis and treatment. In light of this, we want to promote knowledge on this topic while also taking into account the issue of sustainable costs, because only methods affordable for the majority of countries will have wide enough distribution to impact the clinical outcome of women with breast cancer worldwide.

Prof. Tommaso Susini
Prof. Nicoletta Biglia
Guest Editors

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Keywords

breast cancer
prognosis
proliferation
metastasis
molecular analysis
immunohistochemistry
gene expression
survival

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Published Papers (11 papers)

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Editorial

Jump to: Research

4 pages, 197 KiB

Open AccessEditorial

Prognostic Factors Research in Breast Cancer Patients: New Paths

by Tommaso Susini, Nicoletta Biglia and Valentina Elisabetta Bounous

Cancers 2022, 14(4), 971; https://doi.org/10.3390/cancers14040971 - 15 Feb 2022

Cited by 1 | Viewed by 1450

Abstract

Breast cancer is the most frequent tumor among women worldwide [...] Full article

(This article belongs to the Special Issue Prognostic Factors Research in Breast Cancer Patients)

Research

Jump to: Editorial

12 pages, 1271 KiB

Open AccessArticle

The Role of Trastuzumab in Patients with HER2 Positive Small (pT1mi/a) Breast Cancers, a Multicenter Retrospective Study

by Andrea Villasco, Silvia Actis, Valentina Elisabetta Bounous, Fulvio Borella, Marta D’Alonzo, Riccardo Ponzone, Corrado De Sanctis, Chiara Benedetto and Nicoletta Biglia

Cancers 2021, 13(22), 5836; https://doi.org/10.3390/cancers13225836 - 21 Nov 2021

Cited by 4 | Viewed by 2617

Abstract

The treatment with adjuvant Trastuzumab in patients diagnosed with HER2+ small breast cancers is controversial: limited prospective data from randomized trials is available. This study aims to measure the effect of Trastuzumab in the early stages of breast cancer (pT1mic/a pN0/1mi) in terms of disease recurrence and to identify which are the factors that most affect the prognosis of small HER2+ tumors. One hundred HER2+ pT1mic-pT1a breast cancer patients who were treated in three Turin Breast Units between January 1998 and December 2018 were retrospectively selected and reviewed. Trastuzumab was administered to 23 patients. Clinicopathological features and disease-free survival (DFS) were compared between different subgroups. The primary outcome was the disease recurrence rate. Median follow-up time was 86 months. Compared to pT1a tumors, pT1mic lesions had a higher tumor grade (84% of pT1mic vs. 55% of pT1a; p = 0.003), a higher Ki-67 index (81% vs. 46%; p = 0.007) and were more frequently hormone receptor (HR) negative (69% vs. 36%, p = 0.001). Disease recurrence rate was significantly lower among patients who received adjuvant Trastuzumab (p = 0.02), with this therapy conferring an 85% reduction in the risk of relapse (HR 0.15; p = 0.02). Among the patients who did not receive adjuvant Trastuzumab, the only factor significantly associated with an increased risk of developing a recurrence was the immunohistochemical (IHC) subtype: in fact, HR− HER2+ tumors showed a risk seven times higher of relapsing (HR 7.29; p = 0.003). Adjuvant Trastuzumab appears to reduce the risk of disease recurrence even in small HER2+ tumors. The adjuvant targeted therapy should be considered in patients with HR− HER2+ tumors since they have the highest risk of recurrence, independently from size and grade. Full article

(This article belongs to the Special Issue Prognostic Factors Research in Breast Cancer Patients)

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24 pages, 56239 KiB

Open AccessArticle

Potential Therapeutic and Prognostic Values of LSM Family Genes in Breast Cancer

by Hoang Dang Khoa Ta, Wei-Jan Wang, Nam Nhut Phan, Nu Thuy An Ton, Gangga Anuraga, Su-Chi Ku, Yung-Fu Wu, Chih-Yang Wang and Kuen-Haur Lee

Cancers 2021, 13(19), 4902; https://doi.org/10.3390/cancers13194902 - 29 Sep 2021

Cited by 28 | Viewed by 4379

Abstract

In recent decades, breast cancer (BRCA) has become one of the most common diseases worldwide. Understanding crucial genes and their signaling pathways remain an enormous challenge in evaluating the prognosis and possible therapeutics. The “Like-Smith” (LSM) family is known as protein-coding genes, and its member play pivotal roles in the progression of several malignancies, although their roles in BRCA are less clear. To discover biological processes associated with LSM family genes in BRCA development, high-throughput techniques were applied to clarify expression levels of LSMs in The Cancer Genome Atlas (TCGA)-BRCA dataset, which was integrated with the cBioPortal database. Furthermore, we investigated prognostic values of LSM family genes in BCRA patients using the Kaplan–Meier database. Among genes of this family, LSM4 expression levels were highly associated with poor prognostic outcomes with a hazard ratio of 1.35 (95% confidence interval 1.21–1.51, p for trend = 3.4 × 10⁻⁷). MetaCore and GlueGo analyses were also conducted to examine transcript expression signatures of LSM family members and their coexpressed genes, together with their associated signaling pathways, such as “Cell cycle role of APC in cell cycle regulation” and “Immune response IL-15 signaling via MAPK and PI3K cascade” in BRCA. Results showed that LSM family members, specifically LSM4, were significantly correlated with oncogenesis in BRCA patients. In summary, our results suggested that LSM4 could be a prospective prognosticator of BRCA. Full article

(This article belongs to the Special Issue Prognostic Factors Research in Breast Cancer Patients)

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18 pages, 3200 KiB

Open AccessArticle

Immunohistochemical Evaluation of FGD3 Expression: A New Strong Prognostic Factor in Invasive Breast Cancer

by Tommaso Susini, Giulia Saccardin, Irene Renda, Milo Giani, Enrico Tartarotti, Jacopo Nori, Ermanno Vanzi, Elisa Pasqualini and Simonetta Bianchi

Cancers 2021, 13(15), 3824; https://doi.org/10.3390/cancers13153824 - 29 Jul 2021

Cited by 6 | Viewed by 2054

Abstract

Among new prognostic factors for breast cancer, the most promising one seems to be FGD3 (Facio-Genital Dysplasia 3) gene, whose expression improves outcome by inhibiting cell migration. The aim of the study was to evaluate the prognostic role of FGD3 in invasive breast cancer in a series of 401 women, treated at our unit, by evaluating the expression of this gene by immunohistochemistry. Patients with high FGD3 expression showed a significantly better disease-free survival (DFS) (p < 0.001) and overall survival (OS) (p < 0.001). The prognostic value of FGD3 expression was stronger than that of classical pathologic parameters such as histological grade of differentiation, Ki-67 index and molecular subtype. By multivariate Cox analysis, FGD3 expression was confirmed as significant and independent prognostic factor, ranking second after age at diagnosis (≤40 years) for DFS (p = 0.003) and the second strongest predictor of OS, after AJCC Stage (p < 0.001). Our data suggest that inclusion of FGD3 evaluation in the routine workup of breast cancer patients may result in a more accurate stratification of the individual risk. The possibility to assess FGD3 expression by a simple and cheap technique such as immunohistochemistry may enhance the spread of its use in the clinical practice. Full article

(This article belongs to the Special Issue Prognostic Factors Research in Breast Cancer Patients)

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22 pages, 3398 KiB

Open AccessArticle

Cytoplasmic Localization of RXRα Determines Outcome in Breast Cancer

by Alaleh Zati zehni, Falk Batz, Vincent Cavaillès, Sophie Sixou, Till Kaltofen, Simon Keckstein, Helene Hildegard Heidegger, Nina Ditsch, Sven Mahner, Udo Jeschke and Theresa Vilsmaier

Cancers 2021, 13(15), 3756; https://doi.org/10.3390/cancers13153756 - 26 Jul 2021

Cited by 7 | Viewed by 2199

Abstract

The aim of this retrospective study was to assess the prognostic value of cytoplasmic versus nuclear RXRα expression in breast cancer (BC) tissue samples and to correlate the results with clinicopathological parameters. In 319 BC patients, the expression of RXRα was evaluated via immunohistochemistry. Prognosis-determining aspects were calculated through uni- and multivariate analyses. Correlation analysis revealed a trend association with nuclear RXRα expression regarding an improved overall survival (OS) (p = 0.078), whereas cytoplasmic RXRα expression was significantly correlated with a poor outcomes in terms of both OS (p = 0.038) and disease-free survival (DFS) (p = 0.037). Strengthening these results, cytoplasmic RXRα was found to be an independent marker for DFS (p = 0.023), when adjusted to clinicopathological parameters, whereas nuclear RXRα expression was positively associated with lower TNM-staging, i.e., pT (p = 0.01), pN (p = 0.029) and pM (p = 0.001). Additionally, cytoplasmic RXRα expression was positively associated with a higher histopathological tumor grading (p = 0.02). Cytoplasmic RXRα was also found to be a negative prognosticator for Her-2neu-negative and triple-negative patients. Altogether, these findings support the hypothesis that the subcellular localization of RXRα plays an important role in carcinogenesis and the prognosis of BC. The expression of cytoplasmic RXRα is correlated with a more aggressive course of the disease, whereas nuclear RXRα expression appears to be a protective factor. These data may help to identify high-risk BC subgroups in order to find possible specific options in targeted tumor therapy. Full article

(This article belongs to the Special Issue Prognostic Factors Research in Breast Cancer Patients)

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14 pages, 3911 KiB

Open AccessArticle

Impact of Smoking-Related Chronic Obstruction Pulmonary Disease on Mortality of Invasive Ductal Carcinoma Patients Receiving Standard Treatments: Propensity Score-Matched, Nationwide, Population-Based Cohort Study

by Jia-Qiang Zhang, Tsai-Mu Cheng, Wei-Chun Lin, Kuo-Chin Chiu and Szu-Yuan Wu

Cancers 2021, 13(15), 3654; https://doi.org/10.3390/cancers13153654 - 21 Jul 2021

Cited by 4 | Viewed by 2608

Abstract

Purpose: the survival effect of smoking-related chronic obstructive pulmonary disease (COPD) and COPD with acute exacerbation (COPDAE) is unclear for patients with invasive ductal carcinoma (IDC) receiving standard treatments. Methods: we recruited women with clinical stage I–III IDC from the Taiwan Cancer Registry Database who had received standard treatments between 1 January 2009 and 31 December 2018. The time-dependent Cox proportional hazards model was used to analyze all-cause mortality. To reduce the effects of potential confounders when all-cause mortality between Groups 1 and 2 were compared, 1:2 propensity score matching (PSM) was performed. We categorized the patients into two groups based on COPD status to compare overall survival outcomes: Group 1 (current smokers with COPD) and Group 2 (nonsmokers without COPD group). Results: PSM yielded 2319 patients with stage I–III IDC (773 and 1546 in Groups 1 and 2, respectively) eligible for further analysis. In the multivariate time-dependent Cox regression analyses, the adjusted hazard ratio (aHR; 95% confidence interval (CI)) of all-cause mortality for Group 1 compared with Group 2 was 1.04 (0.83–1.22). The aHRs (95% CIs) of all-cause mortality for ≥1 hospitalization for COPDAE within one year before breast surgery was 1.51 (1.18–2.36) compared with no COPDAE. Conclusion: smoking-related COPD was not a significant independent risk factor for all-cause mortality in women with stage I–III IDC receiving standard treatments. Being hospitalized at least once for COPDAE within one year before breast surgery is highly associated with high mortality for women with IDC receiving standard treatments. The severity of smoking-related COPD before treatments for breast cancer might be an important prognostic factor of survival. Thus, the information of the severity of COPD before treatment for breast cancer might be valuable for increasing the survival rate in treatment of breast cancer, especially in the prevention of progress from COPD to COPDAE. Full article

(This article belongs to the Special Issue Prognostic Factors Research in Breast Cancer Patients)

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13 pages, 703 KiB

Open AccessArticle

Expression of X-Linked Inhibitor of Apoptosis Protein (XIAP) in Breast Cancer Is Associated with Shorter Survival and Resistance to Chemotherapy

by Gayathri R. Devi, Pascal Finetti, Michael A. Morse, Seayoung Lee, Alexandre de Nonneville, Steven Van Laere, Jesse Troy, Joseph Geradts, Shannon McCall and Francois Bertucci

Cancers 2021, 13(11), 2807; https://doi.org/10.3390/cancers13112807 - 4 Jun 2021

Cited by 20 | Viewed by 3538

Abstract

XIAP, the most potent inhibitor of cell death pathways, is linked to chemotherapy resistance and tumor aggressiveness. Currently, multiple XIAP-targeting agents are in clinical trials. However, the characterization of XIAP expression in relation to clinicopathological variables in large clinical series of breast cancer is lacking. We retrospectively analyzed non-metastatic, non-inflammatory, primary, invasive breast cancer samples for XIAP mRNA (n = 2341) and protein (n = 367) expression. XIAP expression was analyzed as a continuous value and correlated with clinicopathological variables. XIAP mRNA expression was heterogeneous across samples and significantly associated with younger patients’ age (≤50 years), pathological ductal type, lower tumor grade, node-positive status, HR+/HER2− status, and PAM50 luminal B subtype. Higher XIAP expression was associated with shorter DFS in uni- and multivariate analyses in 909 informative patients. Very similar correlations were observed at the protein level. This prognostic impact was significant in the HR+/HER2− but not in the TN subtype. Finally, XIAP mRNA expression was associated with lower pCR rate to anthracycline-based neoadjuvant chemotherapy in both uni- and multivariate analyses in 1203 informative patients. Higher XIAP expression in invasive breast cancer is independently associated with poorer prognosis and resistance to chemotherapy, suggesting the potential therapeutic benefit of targeting XIAP. Full article

(This article belongs to the Special Issue Prognostic Factors Research in Breast Cancer Patients)

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10 pages, 1570 KiB

Open AccessArticle

Changes in Overall Survival over Time for Patients with de novo Metastatic Breast Cancer

by Toshiaki Iwase, Tushaar Vishal Shrimanker, Ruben Rodriguez-Bautista, Onur Sahin, Anjali James, Jimin Wu, Yu Shen and Naoto T. Ueno

Cancers 2021, 13(11), 2650; https://doi.org/10.3390/cancers13112650 - 28 May 2021

Cited by 11 | Viewed by 3582

Abstract

The purpose of this study was to determine the change in overall survival (OS) for patients with de novo metastatic breast cancer (dnMBC) over time. We conducted a retrospective cohort study with 1981 patients with dnMBC diagnosed between January 1995 and December 2017 at The University of Texas MD Anderson Cancer Center. OS was measured from the date of diagnosis of dnMBC. OS was compared between patients diagnosed during different time periods: 5-year periods and periods defined according to when key agents were approved for clinical use. The median OS was 3.4 years. The 5- and 10-year OS rates improved over time across both types of time periods. A subgroup analysis showed that OS improved significantly over time for the estrogen-receptor-positive/HER2-positive (ER+/HER2+) subtype and exhibited a tendency toward improvement over time for the ER-negative (ER−)/HER2+ subtype. In addition, median OS was significantly longer in patients with non-inflammatory breast cancer (p = 0.02) and patients with ER+ disease, progesterone-receptor-positive disease, HER2+ disease, lower nuclear grade, locoregional therapy, and metastasis to a single organ (all p < 0.0001). These findings showed that OS at 5 and 10 years after diagnosis in patients with dnMBC improved over time. The significant improvements in OS over time for the ER+/HER2+ subtype and the tendency toward improvement for the ER−/HER2+ subtype suggest the contribution of HER2-targeted therapy to survival. Full article

(This article belongs to the Special Issue Prognostic Factors Research in Breast Cancer Patients)

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21 pages, 16944 KiB

Open AccessArticle

Altered Expression of Secreted Mediator Genes That Mediate Aggressive Breast Cancer Metastasis to Distant Organs

by Aparna Maiti, Ichiro Okano, Masanori Oshi, Maiko Okano, Wanqing Tian, Tsutomu Kawaguchi, Eriko Katsuta, Kazuaki Takabe, Li Yan, Santosh K. Patnaik and Nitai C. Hait

Cancers 2021, 13(11), 2641; https://doi.org/10.3390/cancers13112641 - 27 May 2021

Cited by 8 | Viewed by 3383

Abstract

Due to the heterogeneous nature of breast cancer, metastasis organotropism has been poorly understood. This study assessed the specific cancer-related gene expression changes occurring with metastatic breast cancer recurrence to distant organs compared with non-metastatic breast cancer. We found that several secreted mediators encoding genes notably, LCN2 and S100A8 overexpressed at the distant metastatic site spine (LCN2, 5-fold; S100A8, 6-fold) and bone (LCN2, 5-fold; S100A8, 3-fold) vs. primary tumors in the syngeneic implantation/tumor-resection metastasis mouse model. In contrast, the ESM-1 encoding gene is overexpressed in the primary tumors and markedly downregulated at distant metastatic sites. Further digging into TCAGA-BRCA, SCAN-B, and METABRIC cohorts data analysis revealed that LCN2, S100A8, and ESM-1 mediators encoding individual gene expression scores were strongly associated with disease-specific survival (DSS) in the METABRIC cohort (hazard ratio (HR) > 1, p < 0.0004). The gene expression scores predicted worse clinically aggressive tumors, such as high Nottingham histological grade and advanced cancer staging. Higher gene expression score of ESM-1 gene was strongly associated with worse overall survival (OS) in the triple-negative breast cancer (TNBC) and hormonal receptor (HR)-positive/HER2-negative subtype in METABRIC cohort, HER2+ subtype in TCGA-BRCA and SCAN-B breast cancer cohorts. Our data suggested that mediators encoding genes with prognostic and predictive values may be clinically useful for breast cancer spine, bone, and lung metastasis, particularly in more aggressive subtypes such as TNBC and HER2+ breast cancer. Full article

(This article belongs to the Special Issue Prognostic Factors Research in Breast Cancer Patients)

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16 pages, 1990 KiB

Open AccessArticle

Individualized Prediction of Breast Cancer Survival Using Flexible Parametric Survival Modeling: Analysis of a Hospital-Based National Clinical Cancer Registry

by Donsuk Pongnikorn, Phichayut Phinyo, Jayanton Patumanond, Karnchana Daoprasert, Pachaya Phothong and Boonying Siribumrungwong

Cancers 2021, 13(7), 1567; https://doi.org/10.3390/cancers13071567 - 29 Mar 2021

Cited by 5 | Viewed by 2744

Abstract

Prognostic models for breast cancer developed from Western countries performed less accurately in the Asian population. We aimed to develop a survival prediction model for overall survival (OS) and disease-free survival (DFS) for Thai patients with breast cancer. We conducted a prognostic model research using a multicenter hospital-based cancer clinical registry from the Network of National Cancer Institutes of Thailand. All women diagnosed with breast cancer who underwent surgery between 1 January 2010 and 31 December 2011 were included in the analysis. A flexible parametric survival model was used for developing the prognostic model for OS and DFS prediction. During the study period, 2021 patients were included. Of these, 1386 patients with 590 events were available for a complete-case analysis. The newly derived individualized prediction of breast cancer survival or the IPBS model consists of twelve routinely available predictors. The C-statistics from the OS and the DFS model were 0.72 and 0.70, respectively. The model showed good calibration for the prediction of five-year OS and DFS. The IPBS model provides good performance for the prediction of OS and PFS for breast cancer patients. A further external validation study is required before clinical implementation. Full article

(This article belongs to the Special Issue Prognostic Factors Research in Breast Cancer Patients)

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15 pages, 1548 KiB

Open AccessArticle

Single-Cell NGS-Based Analysis of Copy Number Alterations Reveals New Insights in Circulating Tumor Cells Persistence in Early-Stage Breast Cancer

by Tania Rossi, Giulia Gallerani, Davide Angeli, Claudia Cocchi, Erika Bandini, Pietro Fici, Michele Gaudio, Giovanni Martinelli, Andrea Rocca, Roberta Maltoni and Francesco Fabbri

Cancers 2020, 12(9), 2490; https://doi.org/10.3390/cancers12092490 - 2 Sep 2020

Cited by 26 | Viewed by 4142

Abstract

Circulating tumor cells (CTCs) are a rare population of cells representing a key player in the metastatic cascade. They are recognized as a validated tool for the identification of patients with a higher risk of relapse, including those diagnosed with breast cancer (BC). However, CTCs are characterized by high levels of heterogeneity that also involve copy number alterations (CNAs), structural variations associated with gene dosage changes. In this study, single CTCs were isolated from the peripheral blood of 11 early-stage BC patients at different time points. A label-free enrichment of CTCs was performed using OncoQuick, and single CTCs were isolated using DEPArray. Libraries were prepared from single CTCs and DNA extracted from matched tumor tissues for a whole-genome low-coverage next-generation sequencing (NGS) analysis using the Ion Torrent S5 System. The analysis of the CNA burden highlighted that CTCs had different degrees of aberration based on the time point and subtype. CTCs were found even six months after surgery and shared CNAs with matched tumor tissue. Tumor-associated CNAs that were recurrent in CTCs were patient-specific, and some alterations involved regions associated with BC and survival (i.e., gains at 1q21-23 and 5p15.33). The enrichment analysis emphasized the involvement of aberrations of terms, associated in particular with interferon (IFN) signaling. Collectively, our findings reveal that these aberrations may contribute to understanding the molecular mechanisms involving CTC-related processes and their survival ability in occult niches, supporting the goal of exploiting their application in patients’ surveillance and follow-up. Full article

(This article belongs to the Special Issue Prognostic Factors Research in Breast Cancer Patients)

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