DOI: 10.31038/CST.2016115

Abstract

Lysine-Specific Demethylase 2 (LSD2), is a flavin-dependent demethylase which acts on the fourth and ninth lysine residues of the histone protein H3 (H3K4 and H3K9). Its homolog, Lysine-Specific Demethylase 1 (LSD1), has been found to be an oncogene in several cancer pathways; due to the two enzymes’ similar structures, LSD2 can be considered a target for the treatment of human cancers. However, the current literature on LSD2 does not agree upon its function in cancer, i.e., whether it functions as a tumor-suppressor or an oncogene, but rather suggests that it may be integral to pathways that serve both effects in human cancer. This paper discusses five major studies on LSD2 in cancer. The first two directly involve human cancer cell lines and disagree on LSD2’s role; Katz et al. found LSD2 in breast cancer to function as an oncogene while Yang et al. studied LSD2 in lung cancer and found it to be vital to a tumor-suppressive pathway, due to its role as an E3 ligase in the autoubiquitylation of O-GlcNAc Transferase (OGT). The other two studies indicate that LSD2 may play multiple roles in human cancer cell survival; LSD2 was found to work in a feed-forward loop with the Nuclear Factor Kappa-light-chain-enhancer of activated B cells (NF-кB), a protein involved in tumor viability, but found to be underexpressed in glioblastomas, where it acts as a target of microRNA-215 (miR-215), which is vital to the survival of glioblastomas under hypoxic conditions. Finally, LSD2 serves as part of an expression pathway in human stem cell carcinomas that controls chemosensitivity and apoptosis. Ultimately, these results indicate that LSD2 is an important target for further study and may play a crucial role in understanding pathways that illuminate novel treatments for human cancer.

Key words

LSD2/KDM1B/AOF1, oncogene, tumor-suppressor, OGT, NF-кB, miR-215

Introduction

Post-translational modification (PTM) of proteins plays important functional roles in gene expression patterns and various cellular pathways. Gene expression within a cell and the maintenance of cell phenotype is highly regulated, and orchestrated by epigenetic PTM such as histone modification and DNA methylation. Carcinogenesis and tumor expression are heavily dependent on alteration of normal gene expression, and thus epigenetic modifications, such as methylation and demethylation, play an important role in tumor progression [1].

The regulation of methylation state, specifically the insertion and deletion of methyl groups on lysine residues of proteins, is carried out by lysine methyl transferases (KMTs) and lysine-specific demethylases (KDMs), respectively. While they were originally classified as histone-modifying enzymes, their role in PTM of non-histone proteins is increasingly being recognized. The KDMs are divided into two distinct categories – the flavin adenine dinucleotide (FAD) dependent amine oxidases (KDMs 1A and 1B) and the iron-and α-ketoglutarate-dependent KDMs (KDMs 2-6) – based on the mechanism of demethylation each utilizes [2]. The roles that such epigenetic enzymes play in the malignant states of human cancer cells are pressing to elucidate, as these can reveal targets for novel therapeutic cancer treatments.

LSD2/KDM1B/AOF1 is a flavin-dependent, lysine-specific demethylase that functions on the mono- and di-methylated states of histone H3K4 (H3K4me1/2) [3], and also shows demethylase activity against di-methylated H3K9 (H3K9me2) [4]. It is a closely related homolog of a more widely studied protein, LSD1/KDM1A/AOF2, which has been shown to be primarily oncogenic in the context of human cancers [5]. Demethylases have been tied to carcinogenesis as they control epigenetic regulation of processes such as cellular motility, apoptosis, and angiogenesis [1]. However, much of the histone demethylase and non-histone substrate functions of LSD2 have yet be explored, and there is a strong case for further study of the role of LSD2 in cancer.

First, LSD2 is, in both structure and function, similar to LSD1, a protein known for its role as an oncogene [5, 6]. LSD2’s location on chromosome 6, cytoband p22.3[7], an area with high concentrations of chromosomal disarrangements in many types of cancers, also indicates that it may play a role in either the promotion or suppression of tumorigenesis [8]. Additionally, LSD2 has been shown to form a complex with methyltransferases euchromatic histone-lysine N-methyltransferase 2 (EHMT2/G9a) and the histone-lysine N-methyltransferase (NSD3) [3], which have been shown to be upregulated in breast cancers [9].

Current research on LSD2’s role in cancer is nascent and primarily focuses on five LSD2 interactions: LSD2 and its synergy with DNA methyltransferase (DNMT) inhibitors in breast cancer [3, 10], LSD2 and O-GlcNAc transferase (OGT) degradation in lung cancer [11], LSD2 as part of a feed-forward circuit with NF-кB [4], LSD2 as a mediator in glioblastoma tumorigenesis under hypoxic conditions [12], and LSD2 as part of an apoptosis and chemotherapy resistance pathway in cancer stem cells [13]. Additionally, available literature disagrees on the fundamental nature of LSD2’s role in human cancers – it is unknown whether it functions as an oncogene or a tumor-suppressor [10, 11]. LSD2 has been shown to be highly upregulated in breast, colorectal, thyroid, and liver cancers [7], and therefore, the study of LSD2 may lead to the discovery of both epigenetic pathways vital to oncogenes as well as potential therapeutic targets.

LSD2 is a demethylase in the KDM1 family that associates primarily with the body regions of actively transcribed genes [14]. It positively regulates gene transcription through binding chromatin in H3K36me3-enriched coding regions that are downstream of gene promoters [6]. The demethylase consists of three major domains: 1) a SWIRM domain (residues 264-372), 2) a C-terminal catalytic amine oxidase domain (AOD), (residues 372-822), and 3) an N-terminal dual zinc finger domain (residues 50-264) composed of an N-terminal zinc finger, a CW-type zinc finger, and two linker sequences [6] (Figure 1).

LSD2 shares with LSD1 a <25% sequence identity, but has often been grouped with its better-known homolog [16]. The two proteins share some features, such as a SWIRM domain, plasticity of active sites, and a mechanism for catalysis (due to the similarities between their respective AOD regions). However, LSD2 has several defining characteristics distinct from those of LSD1 which merit further investigation into its unique role in cancer proliferation [6].

Structurally, LSD2 has several notable features. The first, the SWIRM domain of LSD2, has a 24% sequence identity with that of LSD1. Significantly, and unlike that of LSD1, the SWIRM domain of LSD2 packs closely to the N-terminal domain. It also lacks a C-terminal helix, which is replaced by a coiled loop that may serve as a secondary binding site for the N-terminal tail of the histone H3. LSD2 also lacks a coiled tower domain, which indicates that LSD2 cannot share LSD1’s cofactor, the corepressor of the RE1-silencing transcription factor (CoREST), or its ability to bind with histone deacetylases (HDAC’s) [6].

LSD2 forms a complex with polymerase II and the SET family histone methyl transferases, NSD3 and G9a, which maintain the methylation status of H3K36 and H3K9, respectively. As part of this complex, LSD2 cofactors with glyoxylate reductase 1 homolog (GLYR1/NPAC), a H3K36me3 reader consisting of a Pro-Trp-Trp- Pro (PWWP) domain, AT-hook motif, and a dehydrogenase domain. This interaction with GLYR1 enhances the demethylase activity of LSD2 at H3K4. The linker region of GLYR1 drives its cofactor activity regardless of the substrate used, indicating that the cofactor has a direct purpose in histone demethylation. GLYR1 has been theorized to operate on the tail of histone H3, and does not alter the shape of LSD2 or of its catalytic domain, thus having no effect on LSD2’s substrate specificity [15].

Analogous to LSD1, whose function can differ depending on its binding partners, LSD2 also serves as an activator of gene expression through its non-histone functions, for example, by being recruited to promoters of inflammatory genes in response to the NF-кB subunit c-Rel. This interaction potentiates demethylation of H3K9, leading to the expression of NF-кB in a forward feedback loop [4].

Methods and Materials

A literature search was carried out using the following search terms: LSD2, AOF1 and KDM1B. In order to be examined in depth, each paper was required to study LSD2, though LSD2 was not required to be part of the primary aim of the paper. However, the interaction between LSD2 and human cancer cells, or LSD2 and a related protein with a relevant pathway in human cancers, must be examined within each paper as one of the aims. Papers that focused primarily on LSD1/ KDM1A/AOF2 were excluded. Papers that discussed LSD2 as part of their primary aim, but did not involve human cancer cells or a known human cancer cell pathway, were also excluded. 67 total papers were found using the above search criteria, and 50 were ruled out for reasons including non-relationship to LSD2 (for example, many papers were instead about lipid-storage droplet 2 or grouped LSD2 with LSD1 as the same protein) and non-relationship to cancer (papers on stem cells, hyperinsulinemia, and other diseases were ruled out). 5 of these papers explicitly investigated LSD2 in cancer, and these are discussed in detail hereafter.

Results

Current literature disagrees on the nature of LSD2 in carcinogenesis

Two major studies have specifically discussed the role of LSD2’s chromatin-remodeling functions in cancers. The first is a study by Katz et al. which examines the interactions of DNMTs and LSD2 in breast cancer [10]; the second by Yang et al. [11] which discusses the role of LSD2 as an E3 ligase in lung cancer. Interestingly, these primary studies differ on their categorization of the role of LSD2 in cancer: Katz denotes it oncogenic while Yang describes it as having tumor-suppressing functions.

LSD2 in breast cancer

In Katz et al.’s investigation of LSD2 in breast cancer, short hairpin RNA (shRNA) was used to produce up to 90% LSD2-knockdown (KD) in MDA-MB-231 breast cancer cells, with no impact on LSD1 expression. A 2D colony-formation assay in MDA-MB-231 and MCF7 cells showed that LSD2-KD led to a 25-50% decrease in colony formation, demonstrating that LSD2 promotes the survival of breast cancer cells, and may have an oncogenic role in breast cancer.

A 30% reduction in acetyl H3K9, a marker of active transcription, was also observed, demonstrating that LSD2-KD cells have lower global levels of DNA methylation. This study also found that nuclear protein lysates from LSD2-KD cells demonstrated lower demethylase activity than those of a scramble-cell control line. Additionally, the expression levels of several DNMTs did not change substantially in LSD2-KD cells, suggesting that the reduced DNA methylation seen in LSD2-KD does not result from the downregulation of protein expression of DNMT’s, but rather the blockade of DNMT activity through LSD2-KD. Thus LSD2-KD and decrease in DNMT activity are closely related in breast cancer.

LSD2 and DNMT inhibition

Katz et al. also examined the synergy between decitabine (DAC), a DNMT inhibitor, and LSD2 inhibition. They found that LSD2-KD cells had a higher sensitivity to DAC, as evidenced by lower IC- 50 values of DAC in LSD2-KD cells. DAC-treated cells exhibited re-expression of the progesterone receptor (PRA) gene (which is usually silenced in breast cancer) as well as increased global protein expression. A combination of LSD2 knockdown, DAC treatment, and tranylcypromine, another DNMT inhibitor, limited growth of MDA-MB-231 cancer cells, due to higher levels of cell death by apoptosis. Thus this combination of DNMT inhibition and LSD2-KD may have therapeutic merit as it induces apoptosis and results in the re-expression of silenced candidate genes in breast cancer cells.

LSD2 as an E3 ligase regulates OGT in a non-histone-dependent manner

The second major study that examines the function of LSD2 in cancer was conducted by Yang et al. in 2015. The study investigated the non-histone demethylase functions of the enzyme in an effort to elucidate the less-examined functions of histone demethylases as a whole. Their first major finding was that LSD2 demonstrates E3 ligase activity through autoubiquitylation of OGT, likely due to the zinc-finger domains specific to the structure of LSD2. Using shRNA, two mutants were produced. One, with the mutation of zinc-chelating residues (C53A/C58A/C92/C95A, LSD24CA) produced cells with E3 ubiquitin ligase activity, but without LSD2 histone demethylase activity. The second had a mutation of two surface residues E71A/R72A of LSD2 (LSD2ER-AA) which largely decreased its E3 ligase activity in an in vitro ubiquitylation assay. The zinc finger domains were needed for both functions, as their mutation resulted in a decrease in both demethylase and E3 ubiquitin ligase activity. However, each function was shown to be independent from the other.

LSD2’s ability to selectively demonstrate E3 ubiquitin ligase activity on OGT indicates that a part of its role in cancer may be through this pathway. OGT, an enzyme involved in O-GlcNAcylation, a process vital to cell growth, and has been shown to encourage the growth of tumor cells [17]. OGT is regulated by LSD2 at a protein level through a ubiquitin-dependent pathway, rather than through regulation of the transcription of OGT, as demonstrated through similar mRNA and expression levels of OGT in human embryonic kidney 293 cells (HEK-293).

shRNA mutants of A549 cells without LSD2 (chosen for their nearly undetectable expression of LSD2 in lab tests) grew larger colonies in soft agar assays, indicating that in lung cancer, LSD2 may selectively inhibit cell growth. The downregulation of OGT in cells in vivo had a similar effect, and the degradation of OGT was shown to be dependent only on LSD2’s E3 ligase activity, indicating that LSD2’s tumor-suppressor properties may be independent of its histone demethylase capabilities and instead dependent upon its E3 ubiquitin ligase activity. Through expression tests, oncogenes involved in the regulation of the cell cycle as well as in some cellular signaling cascades were found to be suppressed by LSD2’s E3 ligase activity. The histone demethylase capabilities of LSD2 were found instead to regulate various functions such as the Wnt receptor signaling pathway, cellular responses to stimuli, cell adhesion, and cellular immune response.

LSD2 is recruited by c-Rel to promoters of inflammatory genes to demethylate H3K9me2 leading to expression of NF-кB-driven gene expression

The interactions of LSD2/KDM1B/AOF1 and NF-кB demonstrate one role of LSD2 in gene activation by demethylation of H3K9me2, and its implications in cancer. While this study by van Essen et al. does not directly involve human cancer cells, NF-кB has been shown to serve a role in many human cancers [9]. LSD2 was found to serve as part of a feed-forward circuit involving the subunits of NF-кB, p65 and c-Rel, and the gene promoters for interleukin-II and Mdc. LSD2 was first found to have H3K9 demethylase activity in addition to H3K4 activity, though to a lesser extent. Its action against dimethyl H3K9 regulates these two genes, interleukin-II and Mdc, which are both targets of NF- кB. van Essen et al. demonstrated that in response to LPS stimulation, LSD2 is actively recruited by c-Rel to target promoters through H3K9 demethylation. Without stimulation, this demethylation occurs when a weak presence of c-Rel, while insufficient to drive transcription on its own, recruits LSD2 to the promoter. Through inhibiting each portion of this pathway, the study demonstrates that through a feed-forward loop, weak c-Rel values result in H3K9 demethylation by LSD2, recruitment of NF-кB with both of its subunits, and activation of interleukin-II and Mdc expression.

LSD2 and microRNA

Another study conducted by Hu et al. describes the interactions between microRNA (miR), glioma-initiating cells (GICs), and LSD2 in glioblastoma (GBM). In this study, miR-215 was found, using a screen, to induce hypoxia in GICs, as well as to mediate their responses under hypoxic conditions. miR-215 has been shown to act differently in different types of cancers, but in GBM has been shown to have tumorigenic capabilities. Hu found that attenuating miR-215 using inhibitors reduced growth rate and the ability to form neurospheres in GBM in both in vitro and in vivo assays. LSD2 is a target of miR- 215, and when it was inhibited with miR-215, GBM tissues showed a significant return of tumor growth. Hu has demonstrated that the miR-215-LSD2 pathway helps to adapt GICs to hypoxic conditions. Paired with the observation that LSD2 is under-expressed in GBM patients and tissues, Hu’s work may indicate that LSD2 serves a tumor-suppressive role in this pathway [12].

LSD2 and head and neck squamous cell carcinoma (HNSCC)

Bourguignon et al. studied cancer stem cell signaling pathways in the context of HNSCC [13]. They demonstrate that LSD1, LSD2, and DNMT1 are downregulated by the Oct4-Sox2-Nanog signaling pathway, which results in gene expression patterns that allow cancer stem cells to be self-renewing and resist apoptosis. The Oct4-Sox4- Nanog signaling pathway is activated by microRNA-302 (miR-302). Inhibition of miR-302 caused the upregulation of LSD1 and LSD2, a decrease in global DNA demethylation, apoptosis, and increased sensitivity to chemotherapy. This suggests that in this pathway in HNSCC, LSD2 serves a tumor-suppressive role. Table 1 summarizes the nature of current literature on LSD2 in cancer.

Table 1. Summary of the functions of LSD2 in cancer

Research Group	Connection to LSD2	Primary Results
Katz et al.	LSD2 in Breast Cancer	LSD2 functions as an oncogene. LSD2 knockdown leads to a 25% percent decrease in colony formation and increases sensitivity to the DNMT inhibitor DAC.
Yang et al.	LSD2 as an E3 Ubiquitin Ligase	LSD2 functions as a tumor-suppressor. LSD2 works as an E3 ubiquitin ligase to regulate OGT, which encourages the growth of tumor cells.
van Essen et al.	LSD2 and NF-кB	LSD2 serves as part of a feed-forward circuit, operating on H3K9 and regulating two target genes of NF-кB. LSD2 is recruited by and helps to recruit c-Rel, a subunit of NF-кB.
Hu et al.	LSD2 and miR-215	LSD2 is targeted by miR-215, which controls GIC responses in GBM under hypoxic conditions. Inhibiting LSD2 along with miR-215 results in an increase in tumor growth.
Bourguignon et al.	LSD2 and miR-302	LSD2 is inhibited by miR-302 in the Oct4-Sox2-Nanog signaling pathway in cancer stem cells. LSD2 upregulation via miR-302 inhibition results in increased apoptosis and chemosensitivity.

Discussion

LSD2/KDM1B/AOF1 has been investigated in cancer primarily in breast, lung, GBM, and HNSCC cell lines. However, the current literature disagrees on the role of LSD2 in cancer as well as the pathways in which its oncogenic or tumor-suppressive properties are found. We found that in most work on histone demethylases in cancer, LSD2 has been grouped with LSD1 as a variant and is less researched in comparison to its homolog [8, 16, 18]. Further research on LSD2/ KDM1B/AOF1 is necessary in order to determine and elaborate on its role in human cancers. However, there are many important implications of available research discussing LSD2.

LSD2 as an oncogene

If LSD2 functions as an oncogene as observed by Katz et al., LSD2 can be considered a potential therapeutic target for the development of new compounds that inhibit its activity. LSD2-specific compounds are as yet uncommon, and many LSD1-targeting compounds also have been shown to also target LSD2 due to the similarities in their catalytic domains [6]. This necessitates further research on known LSD1-specific therapeutic compounds to determine LSD2 specificity, as well as the development of compounds that effectively target LSD2 alone.

LSD2 as a tumor-suppressor

Conversely, LSD2 may have tumor-suppressive functions. This would also have important implications in the development of targeted therapies for histone demethylases. Due to the similarities of structure between LSD2 and LSD1, LSD1-targeted therapies must be reexamined for specificity to LSD2, and modified to ensure that they will not impede tumor-suppressive activity of LSD2. Additionally, LSD2’s tumor-suppressive qualities must be further researched – they may elucidate oncogenes or tumor-promoting pathways that may occur in the absence or dysregulation of LSD2. Furthermore, the LSD2 mechanism can provide models for novel approaches to cancer therapies.

LSD2 has complex non-histone functions that serve multiple roles in carcinogenesis

LSD2’s roles in the OGT pathway in lung cancer, the miR-215 pathway in GBM, and the Oct4-Sox2-Nanog pathway in HNSCC are all tumor-suppressive. However, the summary of LSD2’s functions as examined in this review indicate that LSD2 may serve both roles: that its non-histone functions work to suppress tumors, but other functions including some histone demethylase activity of the protein may promote tumor growth. In this case, further research must be conducted to determine whether each function is independent and can be isolated, in order to create effective therapies that utilize LSD2’s tumor-suppressive functions while targeting its oncogenic ones.

LSD2 may be connected to proteins that are independently involved in cancer pathways

LSD2’s interactions with NF-кB are significant in that NF-кB has been increasingly identified as having a vital role in tumor cell survival. Activation of this protein is common in states of inflammation and malignancy in carcinoma. To a certain extent, the proinflammatory process can reduce tumorigenicity via immune surveillance; however, chronic inflammatory states can work to the advantage of transformed cells by promoting immune escape and prosurvival pathways in cancer [19]. Thus NF-кB works to activate survival genes in cancer cells [20]. LSD2, as part of a feed-forward circuit that controls activation of NF-кB and its target inflammatory genes, and as a previously identified target for oncogenesis, may serve as part of a cell pathway that promotes survival in tumor cells. Beyond this specific case, this interaction between LSD2 and NF-кB indicates that avenues for the exploration of the role of LSD2 in cancer can be found in other such possibly oncogenic or tumor-suppressive pathways or proteins and their connection to LSD2.

Conclusion

The conflicting nature of current literature on LSD2 in cancer, namely the uncertainty of its role as either a tumor-suppressor or an oncogene, presents a challenge, and suggests that LSD2’s function in cancer may be more complicated than previously believed. Therapies targeting LSD2 modeled after research on LSD1 may not prove effective because of the fundamental differences in function between the two proteins. LSD2 provides a method of exploring the complex cellular interactions that create tumors, and thus research involving this demethylase must be expanded. Ultimately, the study of LSD2 may serve an important role in elucidating epigenetic mechanisms behind oncogenesis as well as in illuminating paths to potential therapeutic cancer treatments.

Future Work

Future work on LSD2 may include the use of proteomic studies to categorize and analyze its functions and how they may operate in tumorigenesis. Induced overexpression and knockdown studies in a panel of cancer cell lines as well as in normal cells may provide more insight into the biological and oncological roles of LSD2.

Acknowledgements

The authors would like to acknowledge the Huntsman Cancer Institute, and more specifically the Center for Investigational Therapeutics, for the opportunity to work with LSD2 and for the materials and support required to carry out this review.

Competing Interests

We have no competing interests to declare.

Funding Information

The funding for this manuscript’s production and publication was provided by the Center for Investigational Therapeutics, Huntsman Cancer Institute, University of Utah and Salarius Pharmaceuticals.

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DOI: 10.31038/CST.2016114

Abstract

Background

Cancer has become an increasingly important source of morbidity and mortality in Nigeria; however our country lacks an organized cancer control system. Low awareness about the disease spectrum among health professionals (HCP) and health policymakers (HPM) is among the challenges affecting cancer control in Nigeria. This reflection describes the process of providing cancer education in Nigeria to HCP and HPM, through the Cancer Control in Primary Care (CCPC) course. It also shares our experiences during the planning, and challenges encountered.

Methods

Medical Women’s Association of Nigeria partnered with American Society of Clinical Oncology to deliver cancer education in Akwa Ibom State of Nigeria in February 2016. The main learning objectives were:

• Provide HCP working in Akwa Ibom State with essential knowledge on cancer control
• Provide evidence-based management strategies
• Promote multidisciplinary approach for managing breast and cervical cancers
• Promote the formulation of a cancer control policy in the state
• Share knowledge and experiences with others working in the field

Course lasted 3 days, and featured didactic lectures (n=11); demonstrations and simulations (n=4); and plenary sessions (n=7). Course was planned using emails, phone calls, WhatsApp® chats and text messages.

Results

Course was successful with a daily attendance of >140 participants comprising physicians, nurses and policymakers in primary, secondary, tertiary and private health facilities in the state. Over 97% of the participants had improved their knowledge of cancers through the course. We also identified local priorities for cancer control. Use of multiple approaches to recruitment and funding, as well as working with various local partners were crucial to our success.

Conclusion

Challenges encountered in providing cancer education through this medium include funding, recruitment of participants and event management. Overall, the use of the CCPC course to improve cancer education has proven to be successful, cost-effective and important in building practice networks among HCP and HPM in Akwa Ibom State. We recommend this approach for improving cancer education in resource-limited settings. Outcome of course evaluation will be shared in a different communication.

Key words

Medical Education, Health Resources, Medical Oncology, Text Messaging, Nigeria, Multimedia, Primary Health Care

Introduction

Cancer has become an increasingly important source of morbidity and mortality in Nigeria. This trend is largely attributed to improved survival from infectious diseases, increasing life expectancy, as well as rise in risk factors such as cigarette smoking, physical inactivity, obesity and changing dietary patterns. [1-3] Between 2009 and 2010, 4, 521 new cases of invasive cancers were reported in some population cancer registries, with 66% of the cancer occurring in females. (1) Common cancers in Nigeria include breast, cervical, prostate and colorectal cancers [1,2]. Despite the rising burden of cancer, many countries in sub-Saharan Africa, including Nigeria, do not have organized national cancer control systems [2,4]. The absence of an organized cancer control program has adversely affected patient outcomes in Nigeria [5-7]. Cancer control, as used in this discourse refers to an organized public health approach to reduce cancer burden using evidence-based interventions on the cancer continuum, from prevention to palliation.

One of the challenges affecting the control of cancers is the low awareness about the disease spectrum among health professionals (HCP) in the country. Deficient knowledge, ignorance and inappropriate beliefs are among features of poor cancer awareness among HCP in Nigeria [8,9]. It is not surprising then that only about 12% of physicians in a Nigerian city ever informed their patients about cancer screening.  The level of knowledge and clinical competence of health care providers also affect cancer control in Nigeria. Various researchers have highlighted the inadequate training of Nigerian professionals [10,11] For example, there is only one post-basic nursing training program on oncology in Nigeria, in comparison to more than 14 programs in perioperative and psychiatric nursing [12]. The inadequate competence manifests in advocacy/screening practices [13], patient management, [14] and other aspects of cancer care. Some scholars have emphasized the need to improve the knowledge of HCP regarding cancers, as they are a leading source of information for the rest of the public [13,15,16]. This informed the decision of Medical Women’s Association of Nigeria, Akwa Ibom State Branch (MWAN-AKS) to lead the cancer-related education of health care professionals in the state.

This reflective article seeks to describe the process of providing cancer education in Nigeria to health care professionals and policy makers, through the Cancer Control in Primary Care course. It also shares our experiences in planning and challenges encountered. The outcome of the conference will be shared in a different communication.

About Medical Women’s Association of Nigeria, Akwa Ibom State branch (MWAN – AKS)

MWAN – AKS is a non-governmental, non-political, non-profit organization of female medical doctors and dentists. Established in 1990 MWAN – AKS has over 30 active members in various medical specialties, including public health, internal medicine, surgery, pathology, anesthesia, ophthalmology, etc. The association meets monthly. MWAN-AKS also provides free screening for cervical and breast cancers to women living in Akwa Ibom State as a way of giving back to the community. Through our professional and community interactions, MWAN-AKS has realized the need for improved training of local health professionals in Akwa Ibom State on cancer control, including advocacy, prevention, diagnosis and treatment, palliation as well as research.

The Cancer Control in Primary Care (CCPC) course

In February 2016, MWAN-AKS collaborated with American Society of Clinical Oncology (ASCO) to help improve the cancer-related awareness/competence of health care providers and policy makers in Akwa Ibom State, especially at the primary care level. This is motivated by the recognition of training and education as vital components of efforts to tackle the problem of cancer control in Nigeria. ASCO has an existing program called Cancer Control in Primary Care (CCPC) course. The “CCPC course aims to enable participants to better understand resources for cancer diagnosis and treatment in their country and feel more comfortable referring patients suspected of having cancer to a specialist” [17]. MWAN-AKS applied to ASCO in April 2015 for approval to run the CCPC course in Uyo, Nigeria. Akwa Ibom State (with Uyo as capital) has an estimated population of 5,451,277, 49.2% of whom are women. Majority of the residents come from the Ibibio, Annang and Oro nations. A significant number of residents are farmers and petty traders, although the state has a large public sector [18].

The CCPC course was delivered using a combination of teaching methods. There were didactic lectures with multimedia components (n=11), demonstrations and simulations (n=4), as well as plenary sessions (n=7). The lectures included topics in epidemiology, especially regarding breast and cervical cancers. Lectures were simple, easy to understand and key concepts were explained exhaustively. Short videos, hands-on demonstrations with models and color images were used to improve retention and hold the attention of the participants. Interactive sessions were used to discuss issues such as cancer control framework, inter-professional collaboration and strategies for implementing the lessons from the conference. Furthermore, there were real-life; expository accounts from a cancer survivor, relatives of cancer patients and health professionals who had worked with cancer patients, on their experiences with cancer care in the State and Country. This helped demystify the disease spectrum and set the stage for open discussions.

The course was held over 3 days (February 17-19), with each day lasting 8 hours. Each day of the conference began with a summary and questions from the previous day. Course participants were health care professionals (physicians and nurses), primary health care coordinators in each of the 31 Local Government Areas in Akwa Ibom State as well as students (medical and nursing). The faculty for the course included surgeon (1), family physician (1), Community Physicians (3), Anesthesiologist (1), Obstetrician/Gynecologist (1) and Nurse (1). Funding for the course was largely provided by the American Society of Clinical Oncology (ASCO). Other organizations that supported the conference include Clement Isong Foundation, Obong University, Zitadel Medical Diagnostics, Akwa Ibom State Ministry of Health, University of Uyo Teaching Hospital and Stand-Up to Cancer Foundation.

Conference planning

Communication

The planning of this conference involved individuals in 3 countries (Nigeria, United States and Canada), most of whom were on different time zones. As can be imagined, one challenge was finding a suitable time to hold meetings. We relied heavily on emails, telephone calls, text messaging and social media chats (WhatsApp®). Bulky information (such as programs and budgets) was shared through emails. This helped reduce ambiguity. We held more than 3 conference phone calls during the planning of the conference. We also created a WhatsApp group to facilitate discussions. Urgent information was shared through text messages. We considered this to be the quickest way to reach people as most people have their phones handy. To attract policy makers, personal letters were sent to them and these were followed up with phone calls and reminders via text messaging as the date of the event drew closer.

The following is an estimated use of the respective communication media: E-mails >200; text messages >230; WhatsApp chats >356.

In reflecting on the communication between team members during the planning of the conference, we can say that using multiple media was quite helpful. Given the fact that internet service was not very reliable in Nigeria, members were able to get prompt updates through text messages. It also helped us to be more inclusive in our planning. We are actually thrilled at the capability of social media (WhatsApp®) to aid in the planning of this event. Unfortunately, not all members of our planning committee were able to use WhatsApp®

The planning of this event had dual leadership; one aspect focused on course content and delivery (led by Dr. Eguzo) while the other component focused on course administration (led by Dr. Akwaowo). A local organizing committee was constituted to help with event planning/management, fund raising, recruitment of participants and other logistics. We created sub-committees to look after Registration, Venue, Publicity, Entertainment and Communiqué. The leadership of MWAN-AKS was quite involved, attracting top government functionaries and other medical leaders to the conference. We also involved the national leadership of MWAN in the planning of this conference, as it would reflect on the larger organization.

The main learning objectives for conference delegates were the following:

• To provide health care providers (physicians and nurses) working in primary care in Akwa Ibom State with essential knowledge on cancer control
• To provide evidence-based management strategies
• To promote multidisciplinary approach to help improve care for people dealing with cancers, especially for breast and cervical cancers
• To promote the formulation of a cancer control policy in the State
• Share knowledge and common experiences with others working in the field

We also sought to do a pilot research on the cancer-related experience and expectations of patients, health care professionals and health policymakers in Akwa Ibom State regarding cancer control. In addition, pre-and post-conference questionnaires were designed to gain an understanding of the concerns and priorities of participants. They also assessed how the workshop may influence their professional practice in the future, as well as their evaluation of the speakers/conference organization.

Recruitment

We used a multi-pronged approach to recruit conference participants. Our target was to recruit at least 120 individuals from across the state. First, we worked with the Ministry of Local Government and Chieftaincy Affairs (MOLGCA) to recruit people from the Primary Health Care system. The leadership of MOLGCA contacted the primary health care coordinators in each LGA to send at least 2 individuals (a nurse and the PHC coordinator) to attend. Through the Hospital Management Board, we recruited physicians and nurses who work in the secondary health care sector (general hospitals). We worked with the local branch of Nigerian Medical Association to recruit physicians in private practice. The University of Uyo Teaching Hospital was asked to send resident doctors and nurses to attend the conference. We also recruited students from University of Uyo and Methodist General Hospital School of Nursing, Ituk Mbang.

Individuals who were selected for the course were informed through a combination of methods. Formal circulars/letters were sent from the relevant government agencies. Non-governmental organizations, like the Nigerian Medical Association, used text messaging (SMS) to inform their members. Due to space considerations, we did not open the invitation to everyone who could attend. We had also considered advertising the course using Facebook groups. The conference was well-attended by over 140 individuals daily (17% above target). The majority of participants (51%) were nurses from Akwa Ibom State, especially those working in Primary Health Care facilities across the 31 Local Government Areas in the state.

Challenges

Organizing a workshop of this nature commonly poses some challenges. Getting all planners on the same page was not an easy task, considering the differences in time, location and professional perspectives. The guidelines and conference agenda template provided by ASCO were helpful in focusing our planning. We also kept open minds in welcoming new ideas. One expression that was used frequently during our planning discussions was that ‘nothing is set in stone’. This helped us navigate through many of the interpersonal issues that typically affect event planning.

Funding was another challenge with organizing the conference. Although ASCO had approved a grant for the conference, we had difficulty with accessing funds. This was due to changes in Nigerian banking regulations and other bureaucratic delays. In retrospect, we have learned that it is better to sort out the banking aspect of things at least 4 weeks before the conference starts. In addition, we had difficulties with raising funds locally, as Nigeria was experiencing economic difficulties at the time. Our expectations were to access funds from the government and the oil industry. However, Nigeria was facing economic crises around the time of the conference, thus making it difficult to access funds from that source. It would have been better to explore other potential funders early, especially the banking industry.

Despite contacting the Hospitals Management Board about two months prior to the workshop, most of the physicians expected did not get the letters of invitation. This led to the skewed participation on Day 1 as doctors invited from the Local Government Areas (equivalent to districts) failed to turn up and there were more nurses present. We managed this challenge by marketing the event as a Continuing Medical Education activity (awarding CME points) to all doctors in the state. New invitations were sent via text messages through the Nigerian Medical Association and Association of General and Private Medical Practitioners of Nigeria (AGPMPN) in the State. The Local Organizing Committee also invited members of the private sector within the state capital to the workshop. This led to an increase the number of participants registration. By the second and third days, eighty doctors who were not on the original invitation list participated in the workshop.

We thank the Local Government Service Commission for the donation of their auditorium although we experienced some challenges in using the venue with regards to logistics. Choosing a venue is very important in holding a successful conference [19]. Interestingly, few of the conference participants complained about the challenges with the venue; in fact 97% of them rated the conference to be very successful and impactful. This suggests that enriching a conference with quality content could compensate for deficiencies encountered at the venue. Findings from this conference will be shared in another communication.

Conclusion

Cancer control is an emerging public health concept in Nigeria, given the rising cancer morbidity and mortality. In the midst of significant challenges to cancer control in Nigerian and other resource-limited countries, cancer control workshops, like the CCPC, provide a good starting point to improve cancer care. We used multiple approaches to improve our planning, and explored an array of options to fund the conference. Our approach was very cost-effective and led to the building of important networks among clinicians and policy makers across Akwa Ibom State. We were also able to identify local priorities for cancer control.

Following the successful conclusion of the CCPC conference, MWAN-AKS was commissioned by the Akwa Ibom State Ministry of Health to provide breast and cervical cancer screening services to women in Uyo as part of the 2016 International Women’s Day. Our organization is also making plans to further share the content of this conference with more health providers in the grassroots by organizing step-down workshops in each of the 3 senatorial district in Akwa Ibom State. It is our expectation that we will as well be approved by ASCO to hold the Multidisciplinary Cancer Management Course in 2017. This course will build on the gains made from the CCPC course, and further strengthen our efforts at building a local cancer control system. Finally, in the words of Farmer et al (20), “the time has come to challenge and disprove the widespread assumption that cancer will remain untreated in poor countries”.

References

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DOI: 10.31038/CST.2016113

Abstract

Objective: Fear of recurrence is a phenomenon associated with breast cancer survivorship that has been shown to cause pervasive and prominent distress, and poorer overall quality of life. Determining the factors that predict fear of recurrence is important for understanding its consequences on breast cancer survivors.

Design: This study examined whether certain demographic and medical factors influence and predict a fear of recurrence. The factors included time since diagnosis, age at diagnosis, the stage of breast cancer, and the number and average age of children.

Main outcome measures: Fear of recurrence was measured using the Concerns About Recurrence Scale. Over 3000 participants were recruited online with a final sample of 1116 breast cancer survivors.

Results: Five multiple regression models were performed to explore whether particular demographic and medical variables significantly predicted overall fears and worries associated with role, death, womanhood, and health. All five regression models were significant and analyses revealed commonalities underlying certain fears.

Conclusions: The study identified characteristics of women who may be at greater risk for chronic psychological distress and would benefit from ongoing supportive care.

Key words

breast cancer; fear of recurrence; demographics; children; time since diagnosis; age at diagnosis;

Introduction

Breast cancer is one of the most frequently diagnosed diseases; currently it is estimated that 1 in 9 women in Canada will be diagnosed with breast cancer and that 1 in 29 women will succumb to the disease [1]. With the exception of non-melanoma skin cancers, breast cancer is the second leading cause of death from cancer in Canadian women [1]. Fortunately, due to improvements in screening programs and treatments, death rates in women have decreased considerably since the mid-1980s [2,3]. The survival rate of breast cancer patients is now estimated to be 88% [1] and if diagnosed in an early localized stage, 98% [3]. The increase in breast cancer survivorship rates raises concerns for the quality of life experienced by the survivors. Quality of life in relation to breast cancer survivors refers to their physical, psychological, and social well-being in terms of their health after treatment [4].

Survivorship can be defined as corresponding to the period either following completion of active treatments – surgery, radiation, chemotherapy, or hormonal therapy [5] or immediately following the diagnosis [6]. For our purposes, breast cancer survivorship is defined as the time since diagnosis until death [6]. Additionally, while the term “survivor” can refer to the diagnosed individual as well as individuals providing care, in this study, we are reserving the use of “survivors” to individuals diagnosed with breast cancer, and “caregivers” will be used to refer to individuals who are providing care and support to an individual diagnosed with breast cancer.

A breast cancer diagnosis is a lifelong burden. The diagnosis and treatment of breast cancer are universally viewed as stressful and life-threatening experiences [7]. Moreover, there are long-term pervasive effects and residual symptoms, such as fatigue, neuropathy, and pain, even after successful treatment [5,8]. Other challenges that breast cancer survivors have to endure include the adjustment to life after treatment, having sufficient access to health services and support, and living with the fear of cancer recurrence.

Paradoxically, even though support is often needed more during the adjustment period, it is also often during this period that services provided by health care professionals are greatly reduced [5,9]. Breast cancer survivors move from very frequent to infrequent visits, resulting in increased levels of stress due to apprehension and health-related concerns [5,9]. Indeed, past studies have shown that the stress associated with breast cancer survivorship is an important factor to consider in evaluating survivors’ quality of life following treatment [5]. In fact, it has been reported that survivors have higher emotional distress and lower physical and psychological quality of life [7]. Although social support is often reported in the literature as a determinant of emotional well-being in breast cancer survivors, there is no extensive literature investigating the facets of social support that affect quality of life. According to Fong et al. [9], it is the quality of social support, rather than the quantity, that predicts emotional well-being.

Based on a sample of 157 female breast cancer survivors, Fong et al. [9] assessed their availability to social support and emotional well-being (i.e., depression symptoms, stress, negative and positive affect) at baseline (3 to 6 months post-treatment) and after one year (15 to 18 months post-treatment). They reported that quantity of social support significantly declined over the year, and it was associated with increased depression symptoms and stress. Social support quality generally remained stable, but for participants with declining quality of social support, they found that survivors experienced increased depression symptoms, stress, and negative affect. However, when modeled together, it was found that only change in social support significantly predicted change in depression, stress, and negative affect. In their study, the quality of social support explained an additional 4 to 6% of variance in the emotional well-being outcomes.

Aside from the availability of social support as a determinant of well-being and quality of life, a pervasive dread for survivors is the fear of cancer recurrence. Fear of recurrence is defined as the “fear or worry that cancer will return or progress in the same organ or in another part of the body” [6]. Fear of recurrence can be an intrusive and debilitating stressor for breast cancer survivors, potentially inducing high levels of stress due to the uncertainty of whether there will be a cancer recurrence or metastasis [6]. Previous studies report that approximately 33% to 56% of survivors, regardless of stage of breast cancer diagnosis, have moderate to high risk fears, which are associated with lower quality of life and psychological distress [6,7,10,11].

These fears primarily affect the survivors’ emotional and mental states resulting in debilitating stress and worry. Sometimes the fears are so overwhelming that the survivor has difficulty performing daily and social activities causing impairment that is disproportionate to the actual risk of recurrence [12]. Needless to say, fear of recurrence is a common phenomenon for a diagnosis of any type of cancer. Recently, Wanat et al. [13] conducted a meta-ethnography of 17 qualitative studies published between 1996 and 2014, on patients’ experience with recurrence. The studies included patients from a range of cancer types, with breast and ovarian cancers being the most common. After synthesizing the studies, Wanat et al. [13] identified six constructs that encompassed patients’ experience with recurrence.

The first identified construct was experiencing emotional turmoil following diagnosis, that is, the emotional impact of the diagnosis such as shock, fear, anger, devastation, and hopelessness. Wanat et al. [13] reported that 15 of the 17 studies found that the awareness of the possibility of recurrence did not reduce the emotional impact. The second identified construct was experiencing otherness, which primarily referred to the social impacts that a recurrence had on the patients’ existing relationships (e.g., sharing feelings and emotional and physical suffering with others, managing social lives). Next, it was found that seeking support in the health care system was found to be an important part of patients’ experience. This refers to the relationship between the patient and health care professionals and the access (and understanding) of medical information. The last three identified constructs were adjusting to a new prognosis and uncertain future, finding strategies to deal with recurrence, and facing mortality and pertained to balancing worries of disease progression and possibility of death with hope, regaining control over the cancer, taking responsibility for one’s health, and preserving emotional well-being. Wanat et al. [13] reported that common steps towards preservation of emotional well-being involved stopping activities that induced stress such as employment, and adopting activities that restored emotional balance such as connecting with nature.

In an effort to further understand the pervasiveness that fear of recurrence may have on breast cancer survivors, Bloom, Stewart, Chang, & Banks [14] interviewed 185 breast cancer survivors at two time points (time of diagnosis and again five years later when they were cancer free) to assess their quality of life in four domains: physical, psychological, social, and spiritual. The authors reported a significant decrease in worry about the future. Survivors who did not experience a recurrence or metastasis improved in their physical and mental well-being and 92% of the survivors rated their health as good or excellent after the five-year period.

Later research also corroborated the finding that longer time since diagnosis, although it cannot extinguish the fears and worries, could reduce the extent of fears and worries. In a study conducted by Kornblith et al. [15], younger survivors from 18 to 55 years old, scored significantly worse than survivors 65 years old or more) on a range of quality of life measures, including fear of recurrence. It was reasoned that younger survivors experience more distress due to the responsibilities that they may have as primary caretakers for younger children [15]. Parenting children while coping with breast cancer has been shown to cause lower well-being in breast cancer survivors [16] and young mothers especially, experience greater fears of having a recurrence. In an earlier study, we reported that breast cancer survivors under the age of 35 displayed greater levels of fear of recurrence in all domains [10]. Results suggested that being a mother was associated with greater fear of cancer recurrence, but the age of children (i.e., under or over the age of 18) did not impact the magnitude of fear.

Koch et al. [12] reported similar findings in their examination of fear of recurrence in long-term breast cancer survivors, that is, five or more years since diagnosis. Additionally, they showed that fear of recurrence appeared to be independent of cancer stage. However, most studies on fear of recurrence typically do not report whether the participant’s stage of diagnosis affected her level of fear towards a possible recurrence or metastasis, or whether the fear experienced depends on age at or time since diagnosis.

Recently, Cohee et al. [17] tested the theory that social constraints, that is avoidance of the person or discussion, minimizing concerns, and being critical or expressing discomfort negatively impact cognitive processing, which would ultimately affect overall quality of life and increase distress and negative affect. Based on a sample of 222 young, long-term breast cancer survivors (3 to 8 years post-diagnosis and 45 years of age or younger at time of diagnosis) and their partners, Cohee et al. [17] reported that cognitive processing, as defined by intrusive thoughts and cognitive avoidance, mediated the relationship between social constraints and fear of recurrence. They also examined a number of demographic variables, finding ‘current age’ in the mediation analysis for breast cancer survivors and ‘years of education’ for partners to be relevant predictors. In conclusion, Cohee et al. [17] reported that the demographic variables were not significant predictors for fear of recurrence in the respective mediation models.

While time since diagnosis has generally been reported to be associated with decreased fear and worry, there have been mixed findings in regards to the impact that age of breast cancer diagnosis may have on fear of recurrence. Some studies suggest that all survivors may experience fear of recurrence independently of age, while others, including our group, report that women diagnosed at a younger age tend to have higher psychological distress and lower quality of life which may lead to a greater magnitude of fear of recurrence [10,14,15,18]. Taken together, these findings demonstrate how common fear of recurrence is in survivors and its elusive nature.

Although fear of recurrence is a well-studied topic in the cancer survivorship literature and some correlates have been identified, we have yet to distinguish characteristics that may help identify survivors who are at high-risk for developing a significant fear of recurrence. Understanding this relationship is important because it will help inform whether sufficient services are provided to individuals to alleviate their fears, stress, and concerns. There has been some insight on potential interventions, however. Bower et al. [19] found that mindfulness meditation is efficacious in the short-term in reducing stress, behavioural symptoms, and proinflammatory signalling in premenopausal breast cancer survivors. However, as with other studies in the literature, the longevity of the effects is unclear [19], and more research is needed to prolong intervention effects and identify the parameters and characteristics and interventions appropriate for different cancer populations and age groups. The present study will aim to provide more insight on the determinants of vulnerable groups that would benefit from psychosocial interventions and allow us to develop interventions that guarantee the highest possible well-being and quality of life of breast cancer survivors.

Current Study

Our group has shown that breast cancer survivors who were diagnosed at a young age, had a recent diagnosis, or identified as a mother have a heightened fear of recurrence [10,14–16]. While we have not seen a relationship between the age of children and the extent of fear of recurrence [10], the influence of the number of children in this context has not been explored. As mentioned above, being a mother has been demonstrated to be an important factor in the fear of recurrence due to increased responsibilities such as raising a child; therefore, it is relevant to explore the impact that the number of children at the time of diagnosis may have. Moreover, to our knowledge, the impact of medical variables such as time since diagnosis and stage of diagnosis have not been explored in conjunction with these variables on fear of recurrence in breast cancer survivors.

To address this gap, the current study examined the following demographic and medical variables as possible predictors of fear of recurrence: Time since diagnosis, age at diagnosis, stage of breast cancer, number of offspring, and average age of offspring, as well as their interactions. Based on the literature, we expected a greater fear of recurrence for breast cancer survivors who were diagnosed at a young age, had more than one child at the time of diagnosis, and were diagnosed with a later stage of breast cancer.

Measures

Demographic and medical questionnaires

The demographic questions included age, ethnicity, country of origin, occupation, income, education, number, and age of each child. The medical characteristics were age at diagnosis, time since diagnosis, stage of breast cancer, and type of treatment received. The demographics variables for this study were chosen based on previous literature.

Concerns About Recurrence Scale (CARS [6])

This multidimensional scale was designed to determine to what extent fear of recurrence impacts breast cancer survivors. It also investigates what the sources of those fears may be based on a 30-item questionnaire. The CARS includes five subscales; the first subscale Overall Fear of recurrence is addressed with four questions pertaining to the frequency, potential for upset, consistency, and intensity of fears. These four questions are rated on a 6-point scale ranging from 1 (I don’t think about it at all) to 6 (I think about it all the time).

The other four subscales were designed to measure the source of the fears. This section contains 26 questions with a 5-point scale ranging from 0 (not at all), to 1 (a little), to 2 (moderately), to 3 (a lot) and to 4 (extremely). These four sub-scales include Health Worries, Womanhood Worries, Role Worries, and Death Worries. Health worries address the concerns about future treatment, emotional upset, and physical health. Womanhood worries address body image issues, femininity, sexuality, and identity. Role worries address roles and responsibilities in home life and within the work place. Death worries address the fear that breast cancer could lead to death. Higher scores on all scales indicate greater fears. This scale has demonstrated high validity and internal reliability with a Cronbach’s alpha value of 0.87.

Procedure

Participants completed an on-line survey that was administered through iSurvey.ca. The consent form, which outlined the purpose of the data collection, was completed on-line. The survey took approximately 45 minutes to complete and participants could return to the survey at a later date if not completed. Various other questionnaires were included as part of the survey but for the purposes of this study, only scores associated with the Concerns About Recurrence Scale were analyzed in relation to the demographic and medical variables. This study was approved by the University of Ottawa Research Ethics Board (#04-09-04).

Data Analyses

Multiple regression analyses were used to develop models that predict individual worries (health, womanhood, role, death) and overall fears based on the physical and medical demographic variables – time in years since diagnosis, age, age at diagnosis, stage of breast cancer, number of offspring, and average or median age of offspring. Prior to analysis, the statistical assumptions were reviewed for violations. Participant scores were deemed to be outliers if their associated Mahalanobis Distance was greater than the critical value of χ2 = 16.81 at p < .01

Due to multicollinearity, “age” was removed from the model. The five remaining variables met all assumptions and were entered in one step since we had no reason to expect that any particular variable would have a more or less impact on the results. All analyses were performed using SPSS, V22.

Results

Figure 1, plots A to E, show the frequency distributions associated with each demographic variable. The age of participants at diagnosis (Figure 1A) ranged between 25 to 75 years (M = 48 ± 9 years SD). The participants were diagnosed with stage 0 to stage 3 breast cancer (Figure 1B) with the majority identified with stage 1; stage 4 was excluded due to metastases to other sites. Years since diagnosis ranged from 1 to 28 years (Figure 1C). They reported having between one and five children at the time of diagnosis (Figure 1D) with average age ranging from 1 to 50 years old (Median and Mean age = 18 ± 10 years SD, Figure 1E).

Table 1 provides the overall results of each model, in order of level of significance and variance accounted for. The overall fears subscale produced the greatest strength, explaining 14% of the variance associated with fear of recurrence, followed by Role Worries, Womanhood Worries, Death Worries, and Health Worries; overall the combination of the four Worries was associated with roughly 4% of the variance. See Table 2 for a summary of the zero-order correlations.

Table 1. Overall model summary of multiple regression analyses on CARS subscales.

Subscale	F	P	R2 adj
Overall Fears	35.77	<.001	.135
Role Worries	4.66	<.001	.016
Womanhood Worries	3.28	.006	.010
Death Worries	2.62	.023	.007
Health Worries	2.29	.044	.006

Table 2. Summary of the zero-order correlations on CARS subscales.

	r
	Stage of Diagnosis	Age of Diagnosis	Number of Children at Time of Diagnosis	Average Age of Children at Diagnosis	Years since Diagnosis	Years x Age Interaction
Overall Fears	-.085 to .141 (p < .001)	-.191 (p < .001)	.004 (p = .448)	-.190 (p < .001)	-.253 (p < .001)	.091 (p = .001)
Health Worries	.025 (p – .200)	-.086 (p = .002)	-.009 (p = .388)	-.070 (p = .009)	-.031 (p = .153)	Interaction not tested
Death Worries	.046 (p = .063)	-.088 (p = .002)	.024 (p = .209)	-.070 (p = .010)	-.026 (p = .193)	Interaction not tested
Role Worries	.038 (p = .101)	-.118 (p < .001)	-.001 (p = .484)	-.099 (p < .001)	-.056 (p = .032)	.047 (p = .057)
Womanhood worries	.005 (p = .440)	-.082 (p = .003)	-.036 (p = .116)	-.072 (p = .008)	-.064 (p = .016)	.014 (p = .322)

Table 3 lists the demographic and/or medical characteristics that significantly predicted specific Worries. Neither the number nor the average/median age of offspring contributed significantly to any of the models, suggesting that fear of recurrence is independent of these factors.

Worries related to course of illness

Age at diagnosis had a negative relationship with all Worries and uniquely contributed to Death and Health Worries (see Table 3), suggesting that younger age at diagnosis is associated with more fears and worries specific to the course of illness.

Identity-related fears

Age at diagnosis and Time since diagnosis were found to be common negative predictors for identity-related fears, that is, Role and Womanhood Worries, indicating that more recent diagnoses and younger survivors experience greater fear of recurrence and exhibit greater worries in these specific domains.

As a follow-up test, we entered the individual predictors associated with Role Worries and Womanhood Worries as well as their interaction term; as shown in Table 4, these analyses did not reveal significant interactions and the individual predictors maintained their significance.

    Table 3. Significant predictors determined by the multiple regression analyses.

    * How long it has been since diagnosis of breast cancer in years

Overall fears

Overall fears measure the extent to which women worry about recurrence based on its frequency, intensity, consistency, and potential for upset. The analyses revealed that Time since diagnosis, age at diagnosis, and stage of breast cancer (see Table 4) were significant predictors. Stage of diagnosis contributed uniquely and positively to Overall Fears – higher stage equalled more fear. The results suggest that the more recent the diagnosis, the higher the fear. Moreover, individuals diagnosed at a younger age identified as having more overall fears. Lastly, stage of breast cancer indicated a positive relationship showing that a higher stage of breast cancer was associated with greater fear.

To follow up, we centered the two of the three significant predictors, time since diagnosis and age at diagnosis, and created dummy variables to represent each individual stage in the third significant predictor: stage. With the newly created variables, we created two-way interaction terms to enter in a simple multiple regression model with the original predictors. When accounting for the interactions, only two of the original three predictors remained significant (see Table 4). We also found an interaction between Time since diagnosis and Stage 3 (t = -2.77, p = .006) and Age at diagnosis and Stage 2 (t = -2.18, p = .029). For an illustration of the interactions, see Figure 2.

The literature suggests that fear of recurrence is independent of Stage (e.g., Koch et al., 2014); however, our results suggest that Stage is a significant predictor of Overall fears. To explore the relationship between Stage and the remaining four predictors, we conducted a hierarchical regression analysis, with Stage entered before our set of predictors. Change statistics indicated that Stage accounted for 3.8% (p < .001) and our four predictors accounted for 10.1% of the variance (p < .001) in our model.

Table 4. Regression results after accounting for interaction terms for Overall Fears, Role Worries, and Womanhood Worries

* How long it lias been since diagnosis of breast cancer in years

Discussion

The main objective of this study was to determine whether particular demographic and medical variables predict fear of recurrence in a large sample of breast cancer survivors. In particular, we examined the relations between a selection of demographic and medical variables to fear of recurrence in a sample of first-time breast cancer survivors with children at the time of diagnosis. We hypothesized that the five demographic and medical variables entered into the regression analysis would have varying influences on fear of recurrence and would all be significant predictors of fear and worry in each subscale. While all the models were significant for each subscale, we also found common predictors for certain fears – suggesting that these were related to each other and belong to a broader class of fears.

In our earlier studies (see [10] and [16]), motherhood was a significant predictor of fear of recurrence in breast cancer survivors. For example, Lebel et al. [10] reported that young mothers had a higher fear of recurrence than older mothers or women without children; later Arès et al. [16] found that mothers, more than non-mothers, experienced greater fears both in the short and long term. Arès et al. [16] also explored determinates of higher fear of recurrence in young mothers but did not identify any of significance. Our current study differs from these on a few essential points.

Although we did not intend to examine the effects of motherhood on fear of recurrence per se, based on the literature, we included two unexplored predictors that were related to motherhood that may influence fear of recurrence: Age of children at the time of diagnosis and number of children at the time of diagnosis. In the current study we also employed more stringent inclusion criteria. Notably, all the participants included in the current study were first-time breast cancer survivors without a prior diagnosis of cancer, with children at the time of the diagnosis. Our earlier findings did suggest that ‘age’ was an important factor to consider but was not explored thoroughly. In the current study, age at diagnosis was a common predictor for all subscales, demonstrating that the individual’s age at the time of diagnosis significantly affects fear of recurrence in all domains. This outcome is in agreement with the hypothesis that fears and worries are higher depending on the age of the survivor at diagnosis, that is, younger survivors being associated with greater fears.

In this study the examination of breast cancer survivors who self-identified as mothers more closely, with more stringent inclusion criteria, revealed some nuances. Specifically, age and number of children at the time of diagnosis did not influence the magnitude of fear that the participants experienced in regards to a cancer recurrence. Our results revealed that having children, or more broadly, ‘motherhood’, did not appear to have an impact on the level of fear experienced in first-time breast cancer survivors. Unlike our previous studies which used a younger cut-off and segregated age into categories, our analyses were based on the full range of ages, from 25 to 75 years old. Therefore, the importance and relationship of age and number of children at the time of diagnosis could unfold differently and reflect a finer tuning of the data. Building on our previous work, although mothers may experience higher levels of fear of recurrence [10], the results of the current study exemplifies the complexity of fear of recurrence and breast cancer survivorship, and the importance to consider additional facets and determinants such as cancer history, when exploring this construct.

Time since diagnosis was shown to influence fear of recurrence in specific life domains such as roles and womanhood. That is, participants with a recent diagnosis scored, on average, higher than other participants in terms of their distress towards a potential recurrence. This is not surprising as more recent survivors would have greater concerns, especially in the domains of their roles and responsibilities associated with being a woman. However, studies have shown that such fears and worries tend to dissipate over time [12,14] and supportive care, at least, in the short run, would be very useful.

Stage of breast cancer at diagnosis influenced the extent to which survivors worried about a possible recurrence. Although previous studies have suggested that fear of recurrence is independent of breast cancer stage [7], our data suggest otherwise and indicate that survivors with higher stages of breast cancer are associated with a heightened amount of distress. Higher stages of breast cancer are more threatening to the life of the survivor and have more negative symptoms [1]. This may evoke more uncertainties and worries in breast cancer survivors in regards to the possibility of a recurrence.

The characteristics that did not appear to be associated with greater uncertainties and worries in breast cancer survivors were the number and average or median age of children at diagnosis. In the study conducted by Kornblith et al., [15], more than 50% of the younger breast cancer survivors had children living with them (n = 61), while this was true for only 9% of the older survivors (n = 67). While this study suggests that higher fear and worry in younger mothers could be due to the responsibility of having younger children and being a primary care taker, we did not see this relationship in the current study, using a much larger sample. This outcome suggests that the number of children does not have an important impact on the fears of a mother.

These results are consistent however, with the idea that fears are present in all mothers due to the possibility of leaving their children regardless of their age [10,20] or number of children. In our study, participants had at least one child and at most five children. We reasoned that the number of children would be associated with more distress; however, our findings suggest that it is not the number or age of children that is an important generator of distress in breast cancer survivors who are mothers. In the study conducted by Adams et al. [20] they found that young mothers have the hard task of balancing priorities such as their health and treatment needs as well as the physical and emotional demands of children and family. In addition, communicating the illness to their children was shown to be a difficult task [20]. This may explain the increase in fear and worry in young mothers who are survivors as there is an additional stress to balance with their diagnoses when they have to consider their children in the process [20].

Limitations

One major limitation of this study is the use of the demographic predictor variable, average age of children at the time of diagnosis. This variable represents the average age of all children at the time of diagnosis, which means some meaningful data may be lost or misinterpreted. The impact of having children who are dependent (i.e., infants, toddlers, children, and adolescents) and independent (i.e., young and older adults,) are important factors to consider; however, using an average number may encompass both categories of children. Additionally, we examined and compared the range of ages of the children and the median age of children, to the average age of all children; however, the effects were identical regardless of the metric used. It may be useful in the future to rank the average age of the children based on the standard deviations of the mean of the combined ages. Future studies should also consider examining additional parameters, such as marital status of the mothers, health of children, and availability of caretakers, to fully explore and understand the relationship between motherhood and fear of recurrence.

Another limitation of this study is that this sample only represents English-speaking mothers from North America; in order to generalize this to a larger population a more representative and diverse sample should be used. This study was conducted through an online survey, and while this was earlier thought to limit the demographic to those who had internet access, there are now data showing that this is no longer an issue and online surveys actually reach a larger global group of participants [21]. Using survey methods as a tool for data collection has been shown to be a very reliable and valid method [21].

There are other demographic variables that may influence fear of recurrence that were not considered in this study. These variables include education, marital status, income, social economic status, and social support. Nonetheless, the most significant model found explained 14% of the variance in our data, which may provide some explanation of a causal mechanism between breast cancer characteristics and fear of recurrence.

Implications and Future Directions

While this study is consistent with the literature with respect to predictors of fear of recurrence, it has also demonstrated that while mothers (especially young mothers) have greater fear of recurrence, the number of children and age of children at diagnosis does not affect the amount of fear or worry of the survivor. This highlights instead the need for supportive care programs for breast cancer survivors aimed at protecting those who are at greater risk (for instance young mothers) for chronic psychological distress associated with fear of recurrence. These results have confirmed that younger survivors especially need more priority in this context and indicates the importance of sensitivity towards the individual characteristics of the patient in order to detect whether they are experiencing high emotional distress and the need for early interventions to assist them in managing their fears and worries.

In the current study, we explored several specific interactions in the regression models and our results suggest that there may be a relationship between particular stages of breast cancer diagnosis and certain medical variables. But, it is important to note that although these interactions were significant, they accounted for less than 1% of the variance (see part correlation on Table 4). The majority of our participants were diagnosed with Stage 1 breast cancer, we suggest that future studies explore whether fear differs as a function of stage, treatment, and number of recurrences in more advanced breast cancer diagnoses; and to determine if it is a moderator depending on the age of the survivor at diagnosis, demographics of the survivor’s children (e.g., sex, health, age), and the availability of a caregiver to provide care to the survivor as well as her children at the time of diagnosis. This would allow insight into the detailed levels of the variables tested that are important influences in fear of recurrence. Since fear of recurrence is so prevalent, determining the timing and the different ways to cope with fear of recurrence effectively is imperative to help alleviate fears in breast cancer survivors.

Acknowledgements and Funding Information

We would like to thank Avon Army of Women and Canadian Breast Cancer Research Alliance for their support of this study.

Disclosure statement

No potential conflict of interest was reported by the authors.

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DOI: 10.31038/CST.2016112

Editorial

Tobacco use, most people would say. Smoking tobacco increases the risk of developing many types of cancer and is responsible for approximately one-third of all cancer deaths. The association between tobacco use and lung cancer is well known; lung cancer occurs about 20 times more often in heavy smokers than in nonsmokers [1]. However, many lung cancers are diagnosed in never smokers [2], and most smokers do not develop lung cancer [3,4].

Aging, many epidemiologists would probably say. According to SEER cancer statistics review, 1975-2012, cancer incidence increases dramatically with age [5]. The risk of being diagnosed with cancer is 1 in 128 in people under 30 years old, 1 in 10 in people between 30 and 60, and 1 in 3 in people over 60. The rise is more pronounced for the most common cancers. Breast, colon, lung and prostate cancers are over 150 times, 180 times, 600 times and 2,800 times more frequently diagnosed in people over 60 years old than in people under 30. However, cancer incidence decreases late in life for most cancers; men in their 80s have approximately half the risk of developing prostate cancer than men in their 70s. In addition, the risk of some cancers does not correlate well with age; brain cancer and leukemia are more frequently diagnosed in the first decade of life than in one of the following three decades [5].

The self-renewal capacity of the body tissues, some researchers might say. Tissues with a high self-renewal capacity give rise to cancer almost a million times more often than tissues without this capacity. The incidence of breast, prostate or lung cancer is approximately seven cases per 100 people [5], whereas the incidence of heart cancer is 34 cases per 100 million people [6]. Lung cancer in nonsmokers is about 10,000 times more common than heart cancer in smokers [5,6]. However, some tissues with similar self-renewal capacities have different cancer risks [7].

The accumulation of mutations in oncogenes and tumor suppressor genes, many cancer researchers would conclude [8-10]. However, other cancer researchers would present evidence challenging this theory, e.g., sequencing studies showing zero genetic mutations in human tumor samples, and human studies linking non-mutagenic agents with increased cancer risks [11-16]. It has repeatedly been shown that the risk of developing cancer is increased by a variety of non-mutagenic factors, including hormone therapy (several cancer types) [17-19], drinking very hot beverages (esophageal cancer) [20-22], shift work that involves circadian disruption (breast cancer) [23-25], and exposure to non-ionizing electromagnetic fields (childhood leukemia) [26-31]. Carcinogenesis experiments in laboratory rodents have also shown that non-mutagenic factors can have a major impact on cancer incidence. Implanting foreign bodies of different materials under the skin of rodents leads to the formation of tumors; the shape of the implanted material, but not the composition, determines tumorigenesis [11,32-34]. For example, all mice implanted with Millipore filters with a pore size of 0.025 micrometers developed tumors, whereas none of the animals implanted with filters with pore sizes equal or higher than 0.22 micrometers developed any malignancy [32]. There is also consistent evidence that interruption of nerve connections alters cancer incidence and tumor growth. For example, the early phases of prostate tumor development are prevented by surgical interruption of the sympathetic nervous system [35]. Denervation of the stomach also suppresses gastric tumorigenesis [36].

It is known that cancer is ultimately caused by an uncontrolled cell proliferation that threatens life. The uncontrolled cell division of some cells leads to the accumulation of abnormal cell populations that threaten life by interfering with vital body functions [16]. However, despite decades of research, the main biological cause of such an uncontrolled proliferation remains to be elucidated. Not having the answer to the question raised in this Editorial is a major barrier to reducing the burden of the disease [37]. To be widely accepted, the answer should explain the striking differences in cancer risk by age and among tissues. It should also explain why non-mutagenic agents increase the risk of developing the disease. Cancer Studies and Therapeutics welcomes submissions addressing this key question.

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DOI: 10.31038/CST.2016111

Editorial

Cancer represents one of the most threatening diseases in mankind. It is hazardous enough to endanger the health and lives of a vast population around the world, and constitutes the major cause of death in human. The clinicopathologic features of the disease vary greatly depending on the sites of origin, cell type, tumor staging and even gender, and the response to each treatment modality also differs among cancers and individuals. Establishing personalized treatment regimens for achieving the longest survival with supreme quality of life is the ultimate goal of cancer research and treatment. However, the treatment results of patients suffering from cancer are far from satisfaction because of heterogeneity in response to different therapeutic regimens by tumors. In this regard, more in-depth and long-lasting investigations are definitely needed for overcoming this embarrassing situation.

Year around the year, numerous investigators plunge themselves into the work of cancer research to unveil the most intriguing features of cancer, which provides impetus for innovating concepts and treatment strategies in the management of the disease. So far, a lot of progresses have been made in different aspects of cancer study. For instances, investigations on cancer microenvironments have disclosed some of the most mysterious parts in the pathogenesis and progression, therapeutic resistance, recurrence and metastasis of cancer; studies on molecular biology of miscellaneous cancers prompted targeted therapies by finding some specific marker proteins or molecules in the cancer cell signaling; understandings of clinicopathologic characters of different cancers greatly improved the strategic planning for surgical or non-surgical treatment; introduction of new concepts, strategies, therapeutic agents and special techniques such as induction chemotherapy, concurrent chemoradiotherapy, immnunotherapy and targeted therapies, etc. improved the treatment results and outcomes of assorted human cancers; development of new therapeutic agents added much to the multidisciplinary treatment of malignancies arising in different parts of the body. Lately, precision medicine is likely to be playing important roles in directing cancer research.

Based on our understandings and achievements that have been made in cancer prevention and treatment, it is reasonable to believe that we are getting closer to the goal of curing cancer. However, when we open arms to embrace the bright future of cancer research, we have to realize that there is still a lot to do and a long way to go before we can conquer this horrible disease. Recurrence, metastasis and resistance to various treatment modalities remain to be major challenges, which obstacle the treatment planning and strategic decisions for tumor control, and thus the treatment results and outcomes of various cancers, especially for tumors in the advanced stages. Besides, the mechanisms behind these sophisticated, uncontrollable and notorious biological behaviors are not fully understood. To solve these problems, a broad spectrum of topics and related issues have to be taken into consideration in cancer investigation, most important of which are novel concepts, new methods, new regimens, new therapeutic agents, and alternative approaches for early detection and intervention of cancer. These specific areas are all major focuses of Cancer Studies and Therapeutics (CST).

When pursuing cancer research, we do need a transparent and easy-reaching platform, such as an authentic open access scientific journal, for presenting, exchanging, searching and transmitting new ideas, concepts and methodologies associated with cancer prevention and treatment without any limitation and barrier. Meanwhile, it is necessary to adhere to the principle of open mind, open science and open journal. Our primitive motivation for launching this journal, CST, is to deliver the best communication on the fast moving, and continually evolving, global oncology landscape. To merit this peculiar motivation, we will be aiming at making this journal a real open access platform, capable of providing swift, worldwide, totally free access to the full content of every distributed article without any charge to readers or their institutions for access. Under this policy, readers are authorized to retrieve, read, download, copy, print, disseminate, or link to the full-texts of all articles published in CST.

To be frank, CST is a new member of the journal family relating to cancer research, and there is pretty much to do to develop CST into a scientific journal with high impact and reputation. Looking into the list of the editorial board members of CST, we immediately notice that they are all prominent experts with vast experience in different areas of cancer research, prevention and treatment. As the editor-in-chief, I am confident that, with the rigorous, tight and harmonious cooperation among the all prestigious editorial board members, we can make CST a prosperous and fast-going scientific periodical. It is anticipated, without any doubt, that CST will be becoming a real open access platform with truly open mind and open policy, for presenting, exchanging and circulating new ideas, concepts, regimens, and treatment modalities in the scope of cancer research.