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Journal of Cancer Research and Clinical Oncology

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Ube2l3 expression in human gastric cancer and its clinical significance.

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A comparison study of dynamic [ 18 F]Alfatide II imaging and [ 11 C]MET in orthotopic rat models of glioblastoma

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Promising anticancer activity of cromolyn in colon cancer: in vitro and in vivo analysis

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Prevotella intermedia boosts OSCC progression through ISG15 upregulation: a new target for intervention

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Research Paper Nomograms for Predicting Risk and Survival of Esophageal Cancer Lung Metastases: a SEER Analysis Wenhui He, Youzhen Yu, Ziting Yan, Na Luo, Wenwen Yang, Fanfan Li, Hongying Jin, Yimei Zhang, Xiaoli Ma, Minjie Ma J. Cancer 2024; 15(11): 3370-3380. doi:10.7150/jca.92389 Abstract Full text PDF

Research Paper Differential diagnosis of hepatocellular carcinoma and intrahepatic cholangiocarcinoma by ultrasonography combined with multiphase enhanced computed tomography HaiYing Tian, Yuling Chen, XiaoHai Li, LiNa Zhao, Sha Li, ChunYan Liao, YeTing Wu, Bei Zhang J. Cancer 2024; 15(11): 3362-3369. doi:10.7150/jca.94550 Abstract Full text PDF

Research Paper Dermoscopy-based Radiomics Help Distinguish Basal Cell Carcinoma and Actinic Keratosis: A Large-scale Real-world Study Based on a 207-combination Machine Learning Computational Framework Hewen Guan, Qihang Yuan, Kejia Lv, Yushuo Qi, Yuankuan Jiang, Shumeng Zhang, Dong Miao, Zhiyi Wang, Jingrong Lin J. Cancer 2024; 15(11): 3350-3361. doi:10.7150/jca.94759 Abstract Full text PDF

Research Paper miR-769-3p inhibits cellular proliferation of KSHV-infected SH-SY5Y cells through targeting mTOR Dongdong Cao, Zhaofu Wu, Rui Yang, Lixia Yao, Jinhong Huang, Yufei Ding, Aynisahan Ruzi, Zemin Pan, Yuanming Pan, Dongmei Li, Wenyi Gu, Jinli Zhang J. Cancer 2024; 15(11): 3338-3349. doi:10.7150/jca.93595 Abstract Full text PDF

Research Paper Exosomal SOX21-AS1 Regulates EREG by Sponging miR-451a and Promotes the Malignancy of Pancreatic Ductal Adenocarcinoma Yong Yan, Jinyi Wang, Bin Xu, Jianming Ni, Tu Dai, Liying Wang, Hao Wang, Zhiyuan Hua, Kuan Li, Yongping Zhou J. Cancer 2024; 15(11): 3321-3337. doi:10.7150/jca.95014 Abstract Full text PDF

Research Paper Peripheral Blood Inflammatory Markers as A Reliable Predictor of Gastric Mucosal Metaplasia Change in the Middle-aged Population Chia-Yu Lai, Chieh Lee, Ta-Sen Yeh, Ming-Ling Chang, Yu-Sheng Lin, Tsung-Hsing Chen J. Cancer 2024; 15(11): 3313-3320. doi:10.7150/jca.95159 Abstract Full text PDF

Research Paper ACAT1 promotes proliferation and metastasis of bladder cancer via AKT/GSK3β/c-Myc signaling pathway Tingjun Wang, Gang Wang, Danni Shan, Yayun Fang, Fenfang Zhou, Mengxue Yu, Lingao Ju, Gang Li, Wan Xiang, Kaiyu Qian, Yi Zhang, Yu Xiao, Xinghuan Wang J. Cancer 2024; 15(11): 3297-3312. doi:10.7150/jca.95549 Abstract Full text PDF

Research Paper Identification of crucial genes through WGCNA in the progression of gastric cancer Rui Liu, Jie Liu, Qiang Cao, Yanpeng Chu, Hao Chi, Jun Zhang, Jiangping Fu, Tianchi Zhang, Linguang Fan, Chaozhong Liang, Xiufang Luo, Xiaoli Yang, Bo Li J. Cancer 2024; 15(11): 3284-3296. doi:10.7150/jca.95757 Abstract Full text PDF

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Research Paper Genome Resource of Raspberry Root Rot Pathogen Phytophthora gonapodyides Rishi R. Burlakoti, Sanjib Sapkota, Mark Lubberts J. Genomics 2024; 12: 55-57. doi:10.7150/jgen.94500 [ Abstract ] [ Full text ] [ PDF ]

JCA Top cited papers:

• Anahid Jewett, et al. Dual Functions of Natural Killer Cells in Selection and Differentiation of Stem Cells; Role in Regulation of Inflammation and Regeneration of Tissues. Cited by 62
• Jan Trøst Jørgensen, Maria Hersom.  HER2 as a Prognostic Marker in Gastric Cancer - A Systematic Analysis of Data from the Literature. Cited by 204
• Chikezie O. Madu, Yi Lu . Novel diagnostic biomarkers for prostate cancer. Cited by 223
• Ohtani H, et al. A meta-analysis of the short-and long-term results of randomized controlled trials that compared laparoscopy-assisted and conventional open surgery for colorectal cancer. Cited by 167
• Dario Sangiolo . Cytokine Induced Killer Cells as Promising Immunotherapy for Solid Tumors. Cited by 193
• Sara A. Lari, Henry M. Kuerer . Biological Markers in DCIS and Risk of Breast Recurrence: A Systematic Review. Cited by 131

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Quantitative characterization of breast lesions and normal fibroglandular tissue using compartmentalized diffusion-weighted model: comparison of intravoxel incoherent motion and restriction spectrum imaging

To compare the compartmentalized diffusion-weighted models, intravoxel incoherent motion (IVIM) and restriction spectrum imaging (RSI), in characterizing breast lesions and normal fibroglandular tissue.

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AMD1 promotes breast cancer aggressiveness via a spermidine-eIF5A hypusination-TCF4 axis

Basal-like breast cancer (BLBC) is the most aggressive subtype of breast cancer due to its aggressive characteristics and lack of effective therapeutics. However, the mechanism underlying its aggressiveness re...

NSABP FB-10: a phase Ib/II trial evaluating ado-trastuzumab emtansine (T-DM1) with neratinib in women with metastatic HER2-positive breast cancer

We previously reported our phase Ib trial, testing the safety, tolerability, and efficacy of T-DM1 + neratinib in HER2-positive metastatic breast cancer patients. Patients with ERBB2 amplification in ctDNA had...

Screening mammography performance according to breast density: a comparison between radiologists versus standalone intelligence detection

Artificial intelligence (AI) algorithms for the independent assessment of screening mammograms have not been well established in a large screening cohort of Asian women. We compared the performance of screenin...

Clustering of HR + /HER2− breast cancer in an Asian cohort is driven by immune phenotypes

Breast cancer exhibits significant heterogeneity, manifesting in various subtypes that are critical in guiding treatment decisions. This study aimed to investigate the existence of distinct subtypes of breast ...

Outcomes of sentinel node biopsy according to MRI response in an association with the subtypes in cN1–3 breast cancer after neoadjuvant systemic therapy, multicenter cohort study

This study investigated the feasibility of sentinel lymph node biopsy (SLNB) after neoadjuvant systemic therapy (NAST) in patients with initially high nodal burden.

Meeting Abstracts from the British Society of Breast Radiology annual scientific meeting 2023

This article is part of a Supplement: Volume 26 Supplement 1

Selective omission of sentinel lymph node biopsy in mastectomy for ductal carcinoma in situ: identifying eligible candidates

Sentinel lymph node biopsy (SLNB) is recommended for patients with ductal carcinoma in situ (DCIS) undergoing mastectomy, given the concerns regarding upstaging and technical difficulties of post-mastectomy SL...

Metabolomics assisted by transcriptomics analysis to reveal metabolic characteristics and potential biomarkers associated with treatment response of neoadjuvant therapy with TCbHP regimen in HER2 + breast cancer

This study aimed to explore potential indicators associated with the neoadjuvant efficacy of TCbHP regimen (taxane, carboplatin, trastuzumab, and pertuzumab) in HER2 + breast cancer (BrCa) patients.

Chitin-mediated blockade of chitinase-like proteins reduces tumor immunosuppression, inhibits lymphatic metastasis and enhances anti-PD-1 efficacy in complementary TNBC models

Chitinase-like proteins (CLPs) play a key role in immunosuppression under inflammatory conditions such as cancer. CLPs are enzymatically inactive and become neutralized upon binding of their natural ligand chi...

Serum protein profiling reveals an inflammation signature as a predictor of early breast cancer survival

Breast cancers exhibit considerable heterogeneity in their biology, immunology, and prognosis. Currently, no validated, serum protein-based tools are available to evaluate the prognosis of patients with early ...

U2AF2-SNORA68 promotes triple-negative breast cancer stemness through the translocation of RPL23 from nucleoplasm to nucleolus and c-Myc expression

Small nucleolar RNAs (snoRNAs) play key roles in ribosome biosynthesis. However, the mechanism by which snoRNAs regulate cancer stemness remains to be fully elucidated.

Clinical factors associated with patterns of endocrine therapy adherence in premenopausal breast cancer patients

Patients with hormone receptor positive breast cancer are recommended at least five years of adjuvant endocrine therapy, but adherence to this treatment is often suboptimal. We investigated longitudinal trends...

Correction: Mcl-1 confers protection of Her2-positive breast cancer cells to hypoxia: therapeutic implications

The original article was published in Breast Cancer Research 2016 18 :26

Exploring the dynamic interplay between exosomes and the immune tumor microenvironment: implications for breast cancer progression and therapeutic strategies

Breast cancer continues to pose a substantial worldwide health concern, demanding a thorough comprehension of the complex interaction between cancerous cells and the immune system. Recent studies have shown th...

Establishing conditions for the generation and maintenance of estrogen receptor-positive organoid models of breast cancer

Patient-derived organoid models of estrogen receptor-positive (ER+) breast cancer would provide a much-needed tool to understand drug resistance and disease progression better. However, the establishment and l...

Factors associated with overall survival in breast cancer patients with leptomeningeal disease (LMD): a single institutional retrospective review

Breast cancer-related leptomeningeal disease (BC-LMD) is a dire diagnosis for 5–8% of patients with breast cancer (BC). We conducted a retrospective review of BC-LMD patients diagnosed at Moffitt Cancer Center...

Paradoxical cancer cell proliferation after FGFR inhibition through decreased p21 signaling in FGFR1-amplified breast cancer cells

Fibroblast growth factors (FGFs) control various cellular functions through fibroblast growth factor receptor (FGFR) activation, including proliferation, differentiation, migration, and survival. FGFR amplific...

Correction: The novel phosphatase NUDT5 is a critical regulator of triple-negative breast cancer growth

The original article was published in Breast Cancer Research 2024 26 :23

Temporal changes in mammographic breast density and breast cancer risk among women with benign breast disease

Benign breast disease (BBD) and high mammographic breast density (MBD) are prevalent and independent risk factors for invasive breast cancer. It has been suggested that temporal changes in MBD may impact futur...

Expression- and splicing-based multi-tissue transcriptome-wide association studies identified multiple genes for breast cancer by estrogen-receptor status

Although several transcriptome-wide association studies (TWASs) have been performed to identify genes associated with overall breast cancer (BC) risk, only a few TWAS have explored the differences in estrogen ...

BIRC5 expression by race, age and clinical factors in breast cancer patients

Survivin/BIRC5 is a proliferation marker that is associated with poor prognosis in breast cancer and an attractive therapeutic target. However, BIRC5 has not been well studied among racially diverse population...

Factors associated with engraftment success of patient-derived xenografts of breast cancer

Patient-derived xenograft (PDX) models serve as a valuable tool for the preclinical evaluation of novel therapies. They closely replicate the genetic, phenotypic, and histopathological characteristics of prima...

TMEM120B strengthens breast cancer cell stemness and accelerates chemotherapy resistance via β1-integrin/FAK-TAZ-mTOR signaling axis by binding to MYH9

Breast cancer stem cell (CSC) expansion results in tumor progression and chemoresistance; however, the modulation of CSC pluripotency remains unexplored. Transmembrane protein 120B (TMEM120B) is a newly discov...

Breast cancer survivors suffering from lymphedema: What really do affect to corporeality/body image? A qualitative study

Breast cancer-related lymphedema is currently one of the most serious complications that most affect the quality of life of women undergoing breast cancer. The aim of this study was to explore in-depth the exp...

Correction: a phase 1b study of zilovertamab in combination with paclitaxel for locally advanced/unresectable or metastatic HER2-negative breast cancer

The original article was published in Breast Cancer Research 2024 26 :32

Breast composition during and after puberty: the Chilean Growth and Obesity Cohort Study

Breast density (BD) is a strong risk factor for breast cancer. Little is known about how BD develops during puberty. Understanding BD trajectories during puberty and its determinants could be crucial for promo...

UCHL1 contributes to insensitivity to endocrine therapy in triple-negative breast cancer by deubiquitinating and stabilizing KLF5

Ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) is a deubiquitinating enzyme that regulates ERα expression in triple-negative cancer (TNBC). This study aimed to explore the deubiquitination substrates of UCHL...

Cell morphology best predicts tumorigenicity and metastasis in vivo across multiple TNBC cell lines of different metastatic potential

Metastasis is the leading cause of death in breast cancer patients. For metastasis to occur, tumor cells must invade locally, intravasate, and colonize distant tissues and organs, all steps that require tumor ...

The role of surgical tissue injury and intraoperative sympathetic activation in postoperative immunosuppression after breast-conserving surgery versus mastectomy: a prospective observational study

Breast cancer is the second most common cause of death from cancer in women worldwide. Counterintuitively, large population-based retrospective trials report better survival after breast-conserving surgery (BC...

HER2-low and tumor infiltrating lymphocytes in triple-negative breast cancer: Are they connected?

Most patients with triple-negative breast cancer (TNBC) are not candidates for targeted therapy, leaving chemotherapy as the primary treatment option. Recently, immunotherapy has demonstrated promising results...

Detection of HER2 expression using 99m Tc-NM-02 nanobody in patients with breast cancer: a non-randomized, non-blinded clinical trial

99m Tc radiolabeled nanobody NM-02 ( 99m Tc-NM-02) is a novel single photon emission computed tomography (SPECT) probe with a high affinity and specificity for human epidermal growth factor receptor 2 (HER2). In thi...

How does weight gain since the age of 18 years affect breast cancer risk in later life? A meta-analysis

Early life factors are important risk factors for breast cancer. The association between weight gain after age 18 and breast cancer risk is inconsistent across previous epidemiologic studies. To evaluate this ...

Clinically relevant gene signatures provide independent prognostic information in older breast cancer patients

The clinical utility of gene signatures in older breast cancer patients remains unclear. We aimed to determine signature prognostic capacity in this patient subgroup.

The FBXW7-binding sites on FAM83D are potential targets for cancer therapy

Increasing evidence shows the oncogenic function of FAM83D in human cancer, but how FAM83D exerts its oncogenic function remains largely unclear. Here, we investigated the importance of FAM83D/FBXW7 interactio...

A risk analysis of alpelisib-induced hyperglycemia in patients with advanced solid tumors and breast cancer

Hyperglycemia is an on-target effect of PI3Kα inhibitors. Early identification and intervention of treatment-induced hyperglycemia is important for improving management of patients receiving a PI3Kα inhibitor ...

Overcoming doxorubicin resistance in triple-negative breast cancer using the class I-targeting HDAC inhibitor bocodepsin/OKI-179 to promote apoptosis

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with a poor prognosis. Doxorubicin is part of standard curative therapy for TNBC, but chemotherapy resistance remains an important cl...

PTHrP intracrine actions divergently influence breast cancer growth through p27 and LIFR

The role of parathyroid hormone (PTH)-related protein (PTHrP) in breast cancer remains controversial, with reports of PTHrP inhibiting or promoting primary tumor growth in preclinical studies. Here, we provide...

Small molecule inhibitor targeting the Hsp70-Bim protein–protein interaction in estrogen receptor-positive breast cancer overcomes tamoxifen resistance

Estrogen receptor (ER) positive patients compromise about 70% of breast cancers. Tamoxifen, an antagonist of ERα66 (the classic ER), is the most effective and the standard first-line drug. However, its efficac...

A phase 1b study of zilovertamab in combination with paclitaxel for locally advanced/unresectable or metastatic HER2-negative breast cancer

Zilovertamab is a humanized monoclonal antibody targeting ROR1, an onco-embryonic antigen expressed by malignant cells of a variety of solid tumors, including breast cancer. A prior phase 1 study showed that z...

The Correction to this article has been published in Breast Cancer Research 2024 26 :46

Augmented interpretation of HER2, ER, and PR in breast cancer by artificial intelligence analyzer: enhancing interobserver agreement through a reader study of 201 cases

Accurate classification of breast cancer molecular subtypes is crucial in determining treatment strategies and predicting clinical outcomes. This classification largely depends on the assessment of human epide...

The prostate-specific membrane antigen holds potential as a vascular target for endogenous radiotherapy with [ 177 Lu]Lu-PSMA-I&T for triple-negative breast cancer

Overexpression of prostate-specific membrane antigen (PSMA) on the vasculature of triple-negative breast cancer (TNBC) presents a promising avenue for targeted endogenous radiotherapy with [ 177 Lu]Lu-PSMA-I&T. Thi...

Metabolic adaptation towards glycolysis supports resistance to neoadjuvant chemotherapy in early triple negative breast cancers

Neoadjuvant chemotherapy (NAC) is the standard of care for patients with early-stage triple negative breast cancers (TNBC). However, more than half of TNBC patients do not achieve a pathological complete respo...

Identification of CD160-TM as a tumor target on triple negative breast cancers: possible therapeutic applications

Despite major therapeutic advances, triple-negative breast cancer (TNBC) still presents a worth prognosis than hormone receptors-positive breast cancers. One major issue relies in the molecular and mutational ...

Contrast-enhanced ultrasound to predict malignant upgrading of atypical ductal hyperplasia

A malignancy might be found at surgery in cases of atypical ductal hyperplasia (ADH) diagnosed via US-guided core needle biopsy (CNB). The objective of this study was to investigate the diagnostic performance ...

MRI-based tumor shrinkage patterns after early neoadjuvant therapy in breast cancer: correlation with molecular subtypes and pathological response after therapy

MRI-based tumor shrinkage patterns (TSP) after neoadjuvant therapy (NAT) have been associated with pathological response. However, the understanding of TSP after early NAT remains limited. We aimed to analyze ...

Are better AI algorithms for breast cancer detection also better at predicting risk? A paired case–control study

There is increasing evidence that artificial intelligence (AI) breast cancer risk evaluation tools using digital mammograms are highly informative for 1–6 years following a negative screening examination. We h...

Prognostic impact of HER2 biomarker levels in trastuzumab-treated early HER2-positive breast cancer

Overexpression of human epidermal growth factor receptor 2 (HER2) caused by HER2 gene amplification is a driver in breast cancer tumorigenesis. We aimed to investigate the prognostic significance of manual sco...

The novel phosphatase NUDT5 is a critical regulator of triple-negative breast cancer growth

The most aggressive form of breast cancer is triple-negative breast cancer (TNBC), which lacks expression of the estrogen receptor (ER) and progesterone receptor (PR), and does not have overexpression of the h...

The Correction to this article has been published in Breast Cancer Research 2024 26 :53

Low-dose acetylsalicylic acid reduces local inflammation and tissue perfusion in dense breast tissue in postmenopausal women

One major risk factor for breast cancer is high mammographic density. It has been estimated that dense breast tissue contributes to ~ 30% of all breast cancer. Prevention targeting dense breast tissue has the ...

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April 24, 2024

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New potential avenues for cancer therapies through RNA-binding proteins

by King's College London

A new paper describes the role of two RNA-binding proteins in the development of sarcoma and carcinoma cancers, highlighting the important and emerging role of RNA-binding proteins in cancer research and offering a new avenue for therapeutic targets.

This research was a key component of the Ph.D. thesis of Jen Coleman, an MRC-DTP student who has since won a prize for best Ph.D. thesis. The findings are published in the journal iScience .

The traditional understanding of cancer is of a genetic disease driven largely by mutations to oncogenes, a loss of tumor suppressor genes, or a combination of both. Research in the last decade has also begun to look at RNA-binding proteins, which control what genes are expressed in health and disease.

Two RNA-binding proteins, called LARP4A and LARP4B, which have unclear roles in the development of cancer, was the focus of the new publication from the Conte and Grigoriadis labs at King's.

The authors look at their role in the growth of sarcoma and carcinoma cancers. Blocking LARP4A and LARP4B was found to prevent the formation of cancers tumors, showing that they promote cancer growth. Their research also found that they play different, distinct roles within cancer cells .

Their results highlight for the first time the differences between LARP4A and LARP4B, and their role in cancer development. The authors hope that this can provide new avenues for drugs to therapeutically target LARP4A and LARP4B, and more broadly to realize the importance of RNA-binding proteins in cancer research .

"RNA-binding proteins play crucial roles in almost all aspects of cellular biology and therefore it is not surprising that their dysregulation is linked to cancer. However, it has been difficult to put RNA binding proteins at the forefront of cancer biology. Our results show that two such proteins, LARP4A and LARP4B, promote cancer growth and spread that, if targeted, might contribute to cancer therapy ," said Professor Conte.

The next steps for Conte and Grigoriadis labs will be to focus on further understanding the precise mechanisms that LARP4A and LARP4B use to promote cancer growth, which can be used identify targets for therapies.

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This paper is in the following e-collection/theme issue:

Published on 24.4.2024 in Vol 8 (2024)

Cancer Care Supportive Text Messaging Program (Text4Hope) for People Living With Cancer and Their Caregivers During the COVID-19 Pandemic: Longitudinal Observational Study

Authors of this article:

Original Paper

• Reham Shalaby 1 , MD, PhD   ; 
• Wesley Vuong 2 , MPH   ; 
• Belinda Agyapong 1 , MSc   ; 
• April Gusnowski 2 , BA   ; 
• Shireen Surood 2 , PhD   ; 
• Vincent Agyapong 3 , MD, PhD  

1 Department of Psychiatry, University of Alberta, Edmonton, AB, Canada

2 Alberta Health Services, Addiction & Mental Health, Edmonton, Canada, Edmonton, AB, Canada

3 Department of Psychiatry, Dalhousie University, Halifax, NS, Canada

Corresponding Author:

Vincent Agyapong, MD, PhD

Department of Psychiatry

Dalhousie University

5909 Veterans Memorial Lane, 8th Floor Abbie J Lane Memorial Building

QEII Health Sciences Centre

Halifax, NS, B3H 2E2

Phone: 1 7802157771

Fax:1 9024734887

Email: [email protected]

Background: Cancer is the leading cause of death in Canada, and living with cancer generates psychological demands, including depression and anxiety among cancer survivors and caregivers. Text4Hope-Cancer Care SMS text messaging–based service was provided to people with cancer and caregivers during the COVID-19 pandemic to support their mental health.

Objective: The aim of this study is to examine the clinical effectiveness of and satisfaction with Text4Hope-Cancer Care in addressing mental health conditions among people living with cancer and caregivers.

Methods: The study was conducted in Alberta, Canada. People who were diagnosed or receiving cancer treatment and caregivers self-subscribed to receive 3-months daily supportive cognitive behavioral therapy–based SMS text messages and a web-based survey was sent at designated time points to collect clinical and nonclinical data. The Hospital Anxiety and Depression scale (HADS) was used to examine changes in anxiety and depression symptoms after receiving the service. Satisfaction with the service was assessed using a survey with a Likert scale. Descriptive and inferential statistics were used, and test significance was considered with P ≤.05.

Results: Overall, 107 individuals subscribed to the service, and 93 completed the program (completion rate 93/107, 86.9%). A significant improvement in the anxiety symptoms (HADS-Anxiety [HADS-A] subscale) was reported after 3 months of Text4Hope-Cancer Care ( t 11 =2.62; P =.02), with medium effect size (Hedges g =0.7), but not depression symptoms (HADS-Depression [HADS-D] subscale). Subscribers expressed high satisfaction and agreed that the service has helped them to cope with mental health symptoms and improve their quality of life. Most subscribers read the SMS text messages more than once (30/30, 100%); took time to reflect or took a beneficial action after reading the messages (27/30, 90%); and highly agreed (27/30, >80%) with the value of the received supportive SMS text messages as being relevant, succinct, affirmative, and positive. All subscribers recommended SMS text messaging for stress, anxiety, and depression and for cancer care support (30/30, 100%).

Conclusions: Text4Hope-Cancer Care was well-perceived and effectively addressed anxiety symptoms among people living with cancer and caregivers during the peak of the COVID-19 pandemic. This study provides evidence-based support and insight for policy and stakeholders to implement similar convenient, economic, and accessible mental health services that support vulnerable populations during crises.

International Registered Report Identifier (IRRID): RR2-10.2196/20240

Introduction

Cancer is the leading cause of death and is responsible for 28.2% of all deaths in Canada [ 1 ]. The disease mostly affects Canadians aged 50 years and older, but it can occur at any age [ 1 ]. In 2018, 1.5 million Canadians were living with or survived cancer [ 1 , 2 ]. However, newly diagnosed cases are projected to increase by 40% between 2015 and 2030 [ 1 ].

Living with cancer generates ongoing psychological demands that impose a heavy toll on patients and caregivers (a person who takes care of a patient with cancer) [ 3 ]. Depression and anxiety are common mental health conditions among cancer survivors, with nearly 30% reporting clinical symptoms of depression and 40% for anxiety [ 4 , 5 ]. These numbers vary according to different types of cancers [ 4 , 5 ]. Similar results were found for caregivers, where about 1 in 2 experienced symptoms of depression and anxiety. These rates may be as high as 65% and 91% for mothers of children living with cancer [ 3 , 6 ].

Cancer survivors often report depression and anxiety symptoms, including the fear of the recurrence of cancer, low emotional support, social isolation, and feeling lonely or abandoned after the intensive support during the phase of the treatment [ 4 , 7 - 9 ]. Depression and anxiety symptoms negatively impact the health of cancer survivors and caregivers by eroding quality of life, decreasing treatment compliance, and increasing the risk of morbidity and mortality [ 4 , 8 , 10 ].

Several interventions have been proposed to address psychological symptoms among cancer survivors and caregivers. These interventions can include educational, cognitive, or mindfulness-based therapies which are effective in addressing mental health symptoms [ 11 , 12 ]. However, these interventions (eg, in-person or facilitated by trained personnel) can be costly and time-consuming when compared to mobile-based interventions (eg, internet-based cognitive behavioral therapy (iCBT) or SMS text messages) that do not require a specialist facilitator [ 10 , 13 , 14 ].

Furthermore, a major body of literature suggests that remotely delivered interventions are impactful and effective in improving mental health compared to face-to-face services [ 15 , 16 ]. Web-based resources have been embraced as potential solutions that can cross the likely gap between evidence-based therapies and community practice, the gap which has thrived by stigma, underrecognition of psychological symptoms and lack of trained professionals [ 15 , 17 , 18 ].

SMS text messaging has demonstrated effectiveness in the treatment and prevention of mental disorders among diverse populations [ 19 - 22 ]. SMS text messaging services such as Text4Support effectively reduced the risk of harm to self and other harm symptoms after 6 months of intervention in a randomized controlled trial [ 23 ] and improved distress, anxiety, and depression in clinical samples [ 24 ]. Similarly, the Text4PTSI program has achieved fidelity and significantly reduced psychological distress among public safety personnel post intervention [ 25 , 26 ]. SMS text message–based population-level messaging programs have reported user satisfaction rates of well over 80%, and most subscribers have reported feeling connected to support systems and improving their ability to manage anxiety, depression, and general life issues, suggesting an improvement in mental health literacy [ 15 , 27 - 29 ].

In this project, Text4Hope-Cancer Care SMS text message–based service was provided to people living with cancer and caregivers during the COVID-19 pandemic. The service aimed to support their mental health by providing a daily supportive SMS text message based on cognitive behavioral therapy (CBT) principles. The service is designed to reduce stress, anxiety, and depression symptoms associated with the pandemic among this vulnerable population. In this project, we report the results of the Text4Hope-Cancer Care program regarding its clinical effectiveness in addressing mental health conditions and the satisfaction among people living with cancer and caregivers 3 months after receiving the service.

Study Design and Setting

The study was conducted in Alberta, Canada, where patients diagnosed or receiving cancer treatment and caregivers were eligible to self-subscribe to receive a daily supportive SMS text message for 3 months. The messages were crafted with a CBT framework and were developed by a clinical psychologist, and then reviewed and revised by a multidisciplinary team of psychiatrists, mental health therapists, and counselors who work with patients with cancer and caregivers (Text4Hope-Cancer Care is part of the primary Text4Hope service, which was introduced to support the mental health of the general public during the COVID-19 pandemic among Albertans [ 30 ]).

Examples of the Text4Hope-Cancer Care messages are (1) do things you enjoy—these activities can remind you who you are and take your mind off cancer for a while; (2) advocate for your needs using assertiveness—assertiveness is being respectful to you and the other person. Be direct, nonaggressive, and specific; and (3) cancer affects the whole family—to help you and your family cope, try to maximize quality time together, communicate, and create a schedule together.

Ethical Considerations

Participation in the program was voluntary, and completion of the survey did not preclude receipt of subsequent supportive SMS text messages. Subscribers could opt out of the service at any time, and no incentives or inducements for participating in the program were offered. Further details of the methodology are described in the study protocol [ 31 ]. The study was conducted according to the guidelines of the Declaration of Helsinki. Ethics approval has been granted by the University of Alberta Health Research Ethics Board (Pro00086163).

Data Collection

Data collection was run at baseline, 6 weeks, and 3 months, and subscribers were invited to complete these surveys via a link embedded in the received SMS text message at the designated time points. Survey questions were programmed into Select Survey, a web-based survey tool [ 31 ].

Overall, 107 subscribers participated in Text4Hope-Cancer Care program during the period between March 19, 2020, and December 19, 2022, and 14 subscribers opted out of the service (14/107, 13.1%), leaving 93 who completed the service (program completion rate of 93/107, 86.9%). From Figure 1 , 49 subscribers responded to the surveys across all study time points, yielding a response rate of (49/107, 45.8%). There were a total of 65 eligible surveys received (35 at baseline and 30 at follow-up time points 6 weeks and 3 months), and only 12 subscribers have completed both the baseline and follow-up surveys. Survey questions were designed based on study objectives and available evidence from peer-reviewed literature [ 28 , 29 ]. The survey consisted predominantly of categorical items with Likert-scale responses and few continuously rated items. The items included sociodemographic characteristics such as gender, age, ethnic background, educational level, relationship status, employment status, and housing condition; and COVID-19–related data, such as self-isolation or quarantine due to the pandemic and perspectives regarding the likelihood of contracting COVID-19. The survey additionally included items related to cancer conditions, such as the duration of cancer diagnosis, treatment received for cancer therapy, and treatment postponed due to the COVID-19 pandemic for the participants and the loved ones who were diagnosed with cancer, if any. Clinical and service satisfaction data were also collected.

Outcome Measures

Hospital anxiety and depression scale.

To assess the effectiveness of the Text4Hope-Cancer Care service, the Hospital Anxiety and Depression Scale (HADS) was used and presented with the 2 subscales HADS-Depression (HADS-D) and HADS-Anxiety (HADS-A) [ 32 ]. Each HADS subscale contains 7 items; each item has 4 responses with an ordinal score from 0 to 3 and a total score between 0 and 21 in each subscale, with higher scores denoting higher levels of anxious or depressive state [ 33 ]. Some items have reversed responses (ie, from 3 to 0 [3 items for HADS-D and 5 items for HADS-A]). The scale reports how participants felt and behaved during the past week [ 33 ]. Since the scale is devoid of items related to somatic symptoms or symptoms of severe psychiatric illness, it was designed to detect the common mental disorders of depression and anxiety in the adult population attending medical (nonpsychiatric) outpatient clinics [ 33 - 35 ]. A total score of 0-7 is considered normal, 8-10 is considered borderline abnormal (borderline case), and 11-21 is considered abnormal (case) [ 32 ].

Based on previous studies, the sensitivity and specificity of approximately (0.80) were achieved when a cutoff score of 8 or above was used to define caseness (defined as the possible and probable anxiety disorders and depression among patients in nonpsychiatric hospital clinics [ 32 ]), on both HADS-A and HADS-D subscales [ 34 ]. Cronbach α for HADS-A was 0.83 (ranging from 0.68 to 0.93), and for HADS-D was 0.82 (ranging from 0.67 to 0.90), and the correlation between the 2 subscales was 0.56 [ 34 ]. For this study, the mean scores of HADS subscales were used to detect the differences between the study groups and also to trace changes over time.

Satisfaction Measures

A satisfaction questionnaire was provided to collect data related to the dimensions of the study. The dimensions considered included acceptability of the service (subscriber satisfaction or experience), appropriateness (subscriber feedback related to how helpful the daily messages have been in relation to their mental health and cancer diagnosis during the COVID-19 pandemic), and subscribers’ opinion about the use of technology-based services as part of health care during crises times.

Sample Size Calculation

Using a web-based script [ 36 ], we estimated that the sample size needed to assess the effects of the daily supportive SMS text messages among patients with cancer and caregivers on the outcome variables would be 34 with a projection that the effect size for the reduction in mean HADS-D and HADS-A scores at 3 months from baseline would be 0.2, a population variance of 1.0 for each subscale mean score, a 2-sided significance level α=.05, and a power of 80% (β=.2).

Statistical Analysis

Descriptive statistics were performed, and chi-square or Fisher exact tests were used to define the distribution of categorical sociodemographic and cancer-related factors against 2 groups of subscribers. The first group (completers) refers to those who completed baseline and follow-up surveys, while the second group (noncompleters) refers to those who responded only to 1 survey. A post hoc analysis was run for the categorical variables with more than 2 response options when it showed a significant association, using adjusted residuals and z score test. A corrected P value was reported on this occasion ( P value × number of comparisons). An independent 2-tailed t test was used to compare the continuous data of baseline mean scores of HADS subscales between the completers and noncompleters.

To examine the changes before and after receiving Text4Hope-Cancer Care SMS text messages for the completers group, a paired t test was used to find the difference in the mean scores of anxiety and depression HADS subscales from baseline to follow-up time points. Imputation of the missing data was applied using the Last Observation Carried Forward method, that is, the last observation (6 weeks) was carried forward (imputed) when the latest response (3 months) was missing [ 37 ]. Due to the small sample size of the completers (<20), Hedges g effect size was reported when the result showed significance.

For the satisfaction data, descriptive analysis was run with frequency and percentage for reporting data, using bar graphs. SPSS (version 28; IBM Corp) [ 38 ] was used to perform the statistical analysis and statistical test significance was considered with P ≤.05.

Text4Hope-Cancer Care Subscription Information

At baseline, subscribers were asked (multiple response questions) about their source of knowledge about the Text4Hope-Cancer Care service. The majority heard about the service from a website, such as Alberta Health Services or Mental Health Foundation websites (13/35, 37.1%), followed by social media platforms, such as Facebook and Instagram (Meta Platforms; 7/35, 20.1%). The news (eg, newspaper, web-based articles, and television), advice from a health care professional, and word of mouth (eg, family, friend, and coworker) were equally reported by the subscribers (5/35, 14.3%) each. Other sources such as employers, posters, and public libraries were also reported.

Baseline and Sociodemographic Characteristics

Table 1 presents the results of sociodemographic, cancer-related, and clinical characteristics of the study sample. From the table, (16/48, 33.3%) of the participants were between 50 and 59 years inclusive. Participants were predominantly females (42/48, 87.5%), White (47/48, 97.9%), had attained postsecondary education (40/44, 90.9%), were in a relationship (35/44, 79.5%), had employment (25/44, 56.8%), and owned their homes (30/44, 68.2%).

Regarding COVID-19–related questions, nearly a third of the subscribers reported needing to self-isolate or quarantine during the pandemic (15/48, 31.3%). The majority were neutral regarding the likelihood that they will contract COVID-19 (16/35, 45.7%); however, compared to someone who has not been diagnosed with cancer and is not receiving treatment for cancer, half of the subscribers reported that they would more likely contract COVID-19 (9/18, 50%).

Regarding cancer-related data, there were 18 cancer cases and 17 caregivers responded to the survey at baseline. The duration of having a diagnosis of cancer was majorly split between less than 6 months, and 1 year or more duration (7/18, 38.9%), each. In terms of the received treatment for cancer, the highest proportions were reported for surgery (10/18, 55.6%) and chemotherapy (9/18, 50.0%). Having cancer treatment or surgery postponed due to the COVID-19 pandemic was reported by a few participants (3/18, 16.7%).

In terms of the questions related to the loved ones of the participants, most participants reported having had 3 or more loved ones diagnosed with cancer and received treatment for cancer (9/16, 56.3%); having a loved one passed away due to cancer (14/17, 82.4%); mostly were a partner or a parent (6/17, 35.3%, each); the loved one was diagnosed with cancer for 1 year or more (10/17, 58.8%); having had received either surgery and chemotherapy (6/17, 35.3%), each; and the majority reported having their loved ones’ cancer treatment or surgery postponed due to the COVID-19 pandemic (15/17, 88.2%).

a a: Fisher exact test.

b Multiple response questions with reported relative frequency.

c N/A: not applicable.

d HADS-D: depression subscale of the Hospital Depression and Anxiety scale.

e HADS-A: anxiety subscale of the Hospital Depression and Anxiety scale.

Regarding group differences, only 2 questions from above showed significant differences between completers and noncompleters. A significantly higher proportion of completers reported receiving chemotherapy (6/12, 85.7%) compared to noncompleters (3/23, 27.3%; P =.049). Similarly, there was a significant difference regarding the loved ones who were diagnosed with cancer ( P =.047). Post hoc analysis revealed that the proportion of the participants who had a child diagnosed with cancer who completed 2 (50%) surveys was significantly more than expected when compared to those who completed only 1 (0%) survey among the same group ( z score=2.7; adjusted P =.03).

Regarding the clinical assessment, the independent t test revealed no significant difference between completers and noncompleters at their baseline scores of HADS-D ( t 31 =0.09; P =.93) and HADS-A ( t 31 = 0.28; P =.78) subscales.

Clinical Outcome Results

Table 2 shows the changes in the mean scores of the primary outcome measure subscales, HADS-D and HADS-A, after 3 months from the baseline for participants who completed both the baseline and other follow-up surveys (completers). As illustrated in Table 2 , the participants recorded lower mean scores on both HADS-D and HADS-A subscales at follow-up compared to their mean scores at baseline. However, only the HADS-A subscale was statistically significant ( t 11 =2.62; P =.02), with a medium effect size (Hedges g =0.7).

a HADS-D: depression subscale of the Hospital Depression and Anxiety scale.

b HADS-A: anxiety subscale of the Hospital Depression and Anxiety scale.

Satisfaction Data

The feedback regarding the receptivity and satisfaction with Text4Hope cancer care service was reported by the subscribers at the follow-up time points (n=30), that is, after receiving the service.

Benefits of Text4Hope-Cancer Care SMS Text Messages

Figure 2 demonstrates participants’ satisfaction measure data in relation to their perceived mental and physical health. The figure showed that the majority of the subscribers agreed that the messages have helped them to cope with symptoms related to cancer diagnosis, including stress (23/30, 76.7%), anxiety (21/30, 70%), depression (18/30, 60%), and loneliness (17/30, 56.7%). Similarly, most participants agreed that the supportive SMS text messages helped them feel connected to a support system (25/30, 83.3%), feel hopeful that they can manage issues related to cancer diagnosis (21/30, 72.4%), and that the messages improved their overall mental well-being (23/30, 76.7%). However, only 16 (53.3%) participants agreed that the messages enhanced their quality of life.

Receptivity of the Supportive SMS Text Messages

Figure 3 A demonstrates that most subscribers agreed that the SMS text messages were always or often relevant (20/29, 69%), succinct (24/28, 85.7%), affirmative (24/29, 82.8%), and positive (27/30, 90%).

In regard to reading the SMS text messages and actions taken after, Figures 3 B and 3C show that all subscribers reported reading the messages (30/30, 100%). Similarly, the majority reported their return to read the messages (27/30, 90.0%), and they agreed that after reading the messages, they took time to reflect on the messages (23/30, 76.7%).

Overall Satisfaction With the Received Supportive SMS Text Messages and Preference of Their Schedule

Figure 4 shows that most subscribers were satisfied with the service (28/30, 93.3%), preferred receiving the messages once per day (22/30, 73.3%), and the majority preferred the SMS text messages for a 12-month period (13/30, 43.3%).

Opinions About the Use of Technology-Based Services as Part of Health Care

Figure 5 demonstrates that most subscribers were in agreement that everyone struggling with cancer in times of crisis, such as the COVID-19 pandemic, would recommend technology-based services as part of their health care. The top-rated recommended items were SMS text messaging for stress, anxiety, and depression (13/13, 100%); SMS text messaging for cancer care support (13/13, 100%); and telephone counseling for stress, anxiety, and depression (13/13, 100%). These were followed by consultation via telephone conferencing for physical (12/13, 92.3%) and mental health care (12/13, 92.3%); consultation via videoconferencing for mental health care (12/13, 92.3%); telephone counseling for cancer care support (12/13, 92.3%); and web-based counseling for stress, anxiety, and depression (12/13, 92.3%). Following that, web-based counseling for cancer care support was recommended by 11 (84.6%) participants. Notably, email services were relatively less preferred by the study subscribers, including email messaging and support for stress, anxiety, and depression (8/12, 66.7%), and email messaging and support for cancer care support (8/12, 66.7%).

Principal Findings

This study was designed to address mental health burdens among people living with cancer and caregivers in Alberta, Canada, during the COVID-19 pandemic, using the Text4Hope-Cancer Care service. The study also examined the satisfaction of the end users with the provided service. Overall, 93 subscribers completed the Text4Hope-Cancer Care program, and 49 responded to all surveys across study time points. The principal finding of this study was the significant improvement in anxiety symptoms among the people living with cancer and caregivers who received a daily message for 3 months of Text4Hope-Cancer Care service. Although there was an observed improvement in depressive symptoms after 3 months of receiving daily supportive SMS text messages, the difference was not statistically significant.

Text4Hope cancer care represents a supportive approach provided to a vulnerable population who have been already disadvantaged by their cancer diagnosis during the pandemic time, where operations were canceled, appointments and medical care was disrupted or delayed, and hospitals were closed due to national lockdowns and pandemic obligations [ 3 , 39 , 40 ]. Other research has tapped into the need for mental health support for people living with cancer and caregivers using diverse modalities, such as cognitive‐ or mindfulness‐based, acceptance and commitment, supportive‐expressive, educational, and meaning-centered psychotherapy [ 11 , 41 , 42 ].

Our findings were not different from other SMS text messaging services provided in different contexts. Text4Support, for example, has demonstrated clinical effectiveness in reducing the risk of harm to self and other harm symptoms after 6 months of intervention in a randomized controlled trial [ 23 , 24 ]. The findings from this study, however, contradict findings from other studies in relation to addressing depressive symptoms. In 2 randomized controlled trials that used supportive SMS text messages, patients with depression showed symptom reduction on standardized self-report scales compared to a patient group not receiving messages (with large effect sizes: Cohen d =0.85 and 0.67) [ 21 , 22 ]. This could be explained by the heavy toll that those who live with cancer or caregivers are experiencing, particularly, during the COVID-19 pandemic. It is, however, possible, that the participants’ baseline depression would have deteriorated across the study time points without the daily supportive SMS text messages. Due to ethical considerations, this study did not include a control group who would not have received the supportive messages during the pandemic, to compare them to those who have received the service.

During the COVID-19 pandemic, people need to feel connected to a health support system. Therefore, several initiatives that included SMS text messaging services were provided and have reported comparative effectiveness to our study. Text4Hope service was provided to support the mental health of the general public in Alberta; the service reported quite similar findings to our study, where a significant reduction in stress, anxiety, depression symptoms, and suicidal ideation was achieved [ 14 , 30 , 43 , 44 ]. Another related service, the Text4Hope-Addiction program, was introduced to people living with substance use disorders; the service reported significant improvement in standardized measures for craving, anxiety, and depression in subscribers [ 45 ]. Similarly, the Text4PTSI program significantly reduced psychological distress among public safety personnel postintervention [ 25 , 26 ].

The gap in the health care service experienced by patients living with cancer seems evident and could be attributed to the lack of social and mental health support. A recent systematic review of 33 studies has highlighted the lack of social support, among others, as an exacerbating factor within the social construct for developing depression and anxiety among older patients living with cancer [ 9 ]. Such mental health symptoms, particularly depression, are linked to increased risk of mortality among people living with cancer due to psychosocial reasons such as reduced adherence to therapy and appointments; thus, the accessibility to cancer control activities and mental health support can control cancer incidence, morbidity, and mortality rates [ 1 , 9 ].

Our study noticed that most of the subscribers were recently diagnosed and living with cancer for less than 1 year, compared to the caregiver group, whose loved ones were living with cancer for more than 1 year. This may reflect the critical and intense periods in which these vulnerable groups may need mental health support that can span over the duration of the disease, during its early stages, as seen with people living with cancer, or later as seen with caregivers. From the literature, it was reported that the third to fifth year after diagnosis is a period that typically requires close clinical follow-up, as well as supportive care, compared to 5 years after the diagnosis, where most survivors would likely have completed their treatment [ 1 ].

Another observation in this study is that caregivers whose children were diagnosed with cancer were more committed to completing the follow-up surveys. This was supported by the fact that childhood cancer diagnosis impacts the entire family, who in turn need mental health support [ 46 ]. Aligned with this observation, a population-based cohort study in Ontario reported that the mothers of children with cancer had an increased rate of mental health outpatient visits compared to mothers in the general population [ 46 ]. This observation has persisted over decades of follow-up, reflecting the critical needs along with the commitment of the mothers of children with cancer to the provided mental health support services.

Regarding the satisfaction with the service, study subscribers expressed a high degree of satisfaction with the service in terms of coping with mental health symptoms, such as anxiety and depression and improved overall mental well-being. The subscribers highly agreed with the value of the received supportive SMS text messages, as being relevant, succinct, affirmative, and positive. These results were not different from the satisfaction levels achieved with similar services. Among the users of Text4Mood and Text4Hope, more than 3 in 4 have also endorsed an improvement in their ability to manage anxiety, depression, and general life issues, suggesting an improvement in their resilience and mental health literacy [ 28 , 29 ]. Several SMS text message–based population-level SMS text messaging programs have reported user satisfaction rates of well over 80% [ 15 , 27 , 28 ]. Similarly, most of Text4Mood and Text4Hope respondents reported feeling connected to support systems, as compared to our study [ 28 , 29 ]. In the same context, well above 50% (16/30) of the subscribers reported that the service has improved their quality of life. This parameter is of particular importance in people living with cancer who often report marked unmet survivorship care needs that consequently compromise their quality of life [ 8 ].

Participants’ responses showed satisfaction with the SMS text messages’ content and frequency. Most subscribers read the SMS text messages more than once and took time to reflect or take beneficial action after reading the messages. A similar result was obtained with Text4Hope and Text4Mood services, where more than 1 in 5 reported returning to read the SMS text messages [ 28 , 29 ]. Most subscribers (13/30, 43%) preferred receiving the SMS text messages for a 12-month period, as compared to lower populations who opted for 3 (23%) or 6 (27%) months. This may reflect the significant psychological burden imposed by cancer diagnosis and the ongoing need for psychological support services that give them a sense of belonging and attachment to a health care system, particularly during the tough time of the COVID-19 pandemic. Therefore, the study participants probably opted for an extended length of the service to maintain the same sense of security and belonging.

Seeing the technology services, that could be part of the health care system, support people struggling with cancer during crisis times, SMS text messaging and phone counseling were among the top-rated care services either for mental health issues or cancer-related care. This was not surprising since, nowadays, phones represent an integral part of almost everyone’s life that could facilitate communication and provide channels of support when other conventional lines are obstructed or disrupted due to crises, such as the COVID-19 pandemic. Notably, compared to phone services, email services were relatively less preferred by the study subscribers. This could be attributed to the lack of accessibility to the internet required to access emails, particularly compared to the widely spread phones and available cellular plans.

Digital technology, therefore, introduces future opportunities to support the development of a scalable mental health workforce with the potential to leverage these technologies for integrating into mental health care, particularly for people with severe mental illness and economically disadvantaged communities [ 19 , 47 , 48 ].

Strengths and Limitations

The study is not without limitations. The low number of subscribers to the program was one of the limitations that curbed the evidence of Text4Hope cancer care to be evaluated among the rest of the community of people living with cancer and caregivers. Notwithstanding, the study reached the desired sample size as previously determined. The dropout rate of this study was aligned with other SMS text messaging services, such as Text4Hope Canada, where the dropout rate was similar (13%) and relatively higher than other web-based services (eg, iCBT) with a reported adherence rate of (52.8%) [ 10 , 43 ]. It is also of note that this study did not report on the time points at which the subscribers dropped out of the study (n=14); this information could have been helpful in better understanding the receptivity of the service among the targeted population and supporting the planning of future support services. Additionally, although the response rate was relatively low (49/107, 45.8%), as compared to the program completion rate (93/107, 87%), lower response rates are usually encountered with such web-based surveys, particularly when no monetary incentives were used, as the case in this study [ 43 , 49 , 50 ]. On the other hand, the relatively high response rate is one of the strengths of the study which reflects subscribers’ commitment to provide their feedback; thus, the results of the study could be generalized to all cohorts of the study.

Conclusions

Text4Hope-Ccancer Care represents the health system and community response to close the gap during the pandemic time via providing mental health support to a vulnerable sector of the community during the pandemic time. The service was well-perceived and has successfully achieved significant effectiveness in addressing anxiety symptoms among people living with cancer and caregivers during the peak time of the COVID-19 pandemic. Compared to the costly and time-consuming conventional interventions, the SMS text messaging service represents a scalable, cost-effective intervention that can be used on any mobile technology, does not require technical skills, and does not require expensive data plans. This study provides the necessary evidence-based support and insight for policy and stakeholders to implement and guide future resource allocation to convenient, economic, and accessible mental health services that support vulnerable populations during crises.

Acknowledgments

This study was supported by grants from the Mental Health Foundation, the Calgary Health Trust, the University Hospital Foundation, the Alberta Children’s Hospital Foundation, the Royal Alexandra Hospital Foundation, and the Alberta Cancer Foundation. The funder had no role in the design and conduct of the study, collection, management, analysis, interpretation of the data; preparation, review, and approval of the study; or the decision to submit the results for publication. Support for the project was received from Alberta Health Services and the University of Alberta.

Data Availability

The data sets generated and analyzed during this study are available from the corresponding author on reasonable request.

Authors' Contributions

VA performed the conceptualization. RS, WV, AG, SS, and VA performed data curation. RS and VA performed the formal analysis. VA contributed to the funding acquisition, investigation, and project administration. VA and RS contributed to the methodology. VA performed the supervision. RS contributed to writing—original draft. RS, BA, WV, AG, SS, and VA contributed to writing—review and editing.

Conflicts of Interest

None declared.

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Abbreviations

Edited by A Mavragani; submitted 14.10.23; peer-reviewed by N Lau; comments to author 25.01.24; revised version received 04.02.24; accepted 21.02.24; published 24.04.24.

©Reham Shalaby, Wesley Vuong, Belinda Agyapong, April Gusnowski, Shireen Surood, Vincent Agyapong. Originally published in JMIR Formative Research (https://formative.jmir.org), 24.04.2024.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work, first published in JMIR Formative Research, is properly cited. The complete bibliographic information, a link to the original publication on https://formative.jmir.org, as well as this copyright and license information must be included.

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After 40 years of smoking, she survived lung cancer thanks to new treatments

Yuki Noguchi

Denise Lee on her last day of chemo. In addition to chemo and surgery, she was treated with immunotherapy. She's currently in remission. Denise Lee hide caption

Denise Lee on her last day of chemo. In addition to chemo and surgery, she was treated with immunotherapy. She's currently in remission.

Denise Lee grew up in Detroit in the mid-1970s and went to an all-girls Catholic high school. She smoked her first cigarette at age 14 at school, where cigarettes were a popular way of trying to lose weight.

Instead, her nicotine addiction lasted four decades until she quit in her mid-50s.

"At some point it got up as high as 2.5 packs a day," Lee, 62, recalls.

Yet she didn't think about lung cancer risk — until she saw a billboard urging former smokers to get screened. Lee, a retired lawyer living in Fremont, Calif., used to drive past it on her way to work.

"The thing that caught my attention was the fact that it was an African American female on the front," she recalls.

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The american cancer society says more people should get screened for lung cancer.

She eventually got the low-dose CT scan recommended for current and former smokers. When doctors found an early, but dangerous, tumor, Lee cried and panicked. Her mother had cared for her father, who'd died of prostate cancer. "My biggest concern was telling my mom," she says.

But that was six years ago, and Lee is cancer free today. Surgery removed the 2-inch tumor in her lung, then new treatments also boosted her immune system, fighting off any recurrence.

Lung cancer remains the most lethal form of the disease, killing about 135,000 Americans a year – more than breast, prostate and colon cancer combined – which is why many people still think of a diagnosis as synonymous with a death sentence. But with new treatments and technology, the survival rates from lung cancer are dramatically improving, allowing some patients with relatively late-stage cancers to live for years longer.

"If you're gonna have lung cancer, now is a good time," Lee says of the advances that saved her.

Denise Lee has been cancer-free for six years. She says she's grateful she got screened and caught her lung cancer early enough that treatment has been effective. Denise Lee hide caption

Denise Lee has been cancer-free for six years. She says she's grateful she got screened and caught her lung cancer early enough that treatment has been effective.

The key breakthrough, says Robert Winn, a lung cancer specialist at Virginia Commonwealth University, is the ability to better pinpoint the mutations of a patient's particular form of cancer. In the past, treatments were blunt tools that caused lots of collateral damage to healthy parts of the body while treating cancer.

"We've gone from that to molecular characterization of your lung cancer, and it has been a game changer," Winn says. "This is where science and innovation has an impact."

One of those game-changing treatments is called targeted therapy . Scientists identify genetic biomarkers in the mutated cancer cells to target and then deliver drugs that attack those targets, shrinking tumors.

CRISPR gene-editing may boost cancer immunotherapy, new study finds

Another is immunotherapy, usually taken as a pill, which stimulates the body's own defense system to identify foreign cells, then uses the immune system's own power to fight the cancer as if it were a virus.

As scientists identify new cancer genes, they're creating an ever-broader array of these drugs.

Combined, these treatments have helped increase national survival rates by 22% in the past five years – a rapid improvement over a relatively short time, despite the fact that screening rates are very slow to increase. Winn says as these treatments get cheaper and readily available, the benefits are even reaching rural and Black populations with historic challenges accessing health care.

The most remarkable thing about the drugs is their ability to, in some cases, reverse late-stage cancers. Chi-Fu Jeffrey Yang, a thoracic surgeon at Massachusetts General Hospital and faculty at Harvard Medical School, recalls seeing scans where large dark shadows of tumor would disappear: "It was remarkable to see the lung cancer completely melting away."

To Yang, such progress feels personal. He lost his beloved grandfather to the disease when Yang was in college. If he were diagnosed today, he might still be alive.

"Helping to take care of him was a big reason why I wanted to be a doctor," Yang says.

But the work of combating lung cancer is far from over; further progress in lung cancer survival hinges largely on getting more people screened.

Low-dose CT scans are recommended annually for those over 50 who smoked the equivalent of a pack a day for 20 years. But nationally, only 4.5% of those eligible get those scans , compared to rates of more than 75% for mammograms.

Andrea McKee, a radiation oncologist and spokesperson for the American Lung Association, says part of the problem is that lung cancer is associated with the stigma of smoking. Patients often blame themselves for the disease, saying: "'I know I did this to myself. And so I don't I don't think I deserve to get screened.'"

McKee says that's a challenge unique to lung cancer. "And it just boggles my mind when I hear that, because, of course, nobody deserves to die of lung cancer."

Denise Lee acknowledges that fear. "I was afraid of what they would find," she admits. But she urges friends and family to get yearly scans, anyway.

"I'm just so grateful that my diagnosis was early because then I had options," she says. "I could have surgery, I could have chemotherapy, I could be a part of a clinical trial."

And all of that saved her life.

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New study uncovers lasting financial hardship associated with cancer diagnosis for working-age adults in the U.S.

A new study led by researchers at the American Cancer Society (ACS) highlights the lasting financial impact of a cancer diagnosis for many working-age adults and their families in the United States. It shows a cancer diagnosis and the time required for its treatment can result in employment disruptions, loss of household income and loss of employment-based health insurance coverage, leading to financial hardship. When combined with high out-of-pocket costs for cancer care, nearly 60% of working-age cancer survivors report at least one type of financial hardship, such as being unable to afford medical bills, distress and worry, or delaying or forgoing needed care because of cost. The findings are published in CA: A Cancer Journal for Clinicians.

"While the rising costs of cancer care and subsequent medical financial hardship for cancer survivors and families are well-documented in the United States, little attention has been paid to how employment and household income can be affected by a cancer diagnosis and treatment," said lead study author Dr. Robin Yabroff, scientific vice president, health services research at the American Cancer Society. "With nearly half of cancer survivors of working age and not yet age-eligible for Medicare coverage, understanding the potential effects of cancer diagnosis and treatment on employment, income, and access to employer-based health insurance coverage is essential."

Study researchers used a composite patient case to illustrate the potential adverse consequences of cancer diagnosis and treatment, including employment disruptions while receiving cancer care, loss of income for unpaid time away from work, and loss of access to employment-based health insurance coverage, if unable to maintain employment. The authors also summarize existing research and provide nationally representative estimates of multiple aspects of financial hardship from 2019-2021, the most recently available years of the National Health Interview Survey (NHIS). The NHIS collects information about health conditions, including but not limited to cancer diagnoses, health status, employment, health insurance, socioeconomic status and experience with health care from nearly 90,000 individuals in 35,000 households each year.

"There are opportunities for a variety of stakeholders to mitigate financial hardship and assist patients with cancer and their families," added Dr. Yabroff. "Federal, state and local policies can increase availability of comprehensive and affordable health insurance coverage and ensure job protections for working adults."

"Today's findings reiterate the critical role access to affordable, quality care and paid family medical leave plays in reducing the financial toll of cancer on those diagnosed -- particularly while they are of working age," said Lisa Lacasse, president of the American Cancer Society Cancer Action Network (ACS CAN). "A majority of cancer patients and survivors (74%) report being forced to miss work due to their illness, most of whom report missing more than four weeks of work, according to an ACS CAN study. No one should be forced to choose between their treatment and their employment. To truly protect patients from the high costs of cancer, Congress must enact paid family and medical leave as well as provide tangible options for affordable health coverage outside of employer-sponsored plans by making permanent the enhanced Marketplace subsidies that allow millions who otherwise have no affordable coverage option to enroll in Marketplace plans."

Study authors emphasize that employers, cancer care delivery organizations and non-profit organizations can also guide efforts to help patients with cancer avoid financial hardship. Employers can offer robust coverage and benefits options, paid and unpaid leave and other workplace accommodations to help reduce employment disruptions and loss of income during cancer treatment. Within cancer care delivery, providers can screen patients for financial hardship, connect patients with relevant services, and make referrals for occupational medicine, rehabilitation care and physical therapy to facilitate return to work and usual activities during and after cancer treatment.

Other ACS authors involved in this study include: Jingxuan Zhao, Dr. Xuesong Han and Dr. Zhiyuan Zheng.

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Story Source:

Materials provided by American Cancer Society . Note: Content may be edited for style and length.

Journal Reference :

• K. Robin Yabroff, Joanna F. Doran, Jingxuan Zhao, Fumiko Chino, Ya‐Chen Tina Shih, Xuesong Han, Zhiyuan Zheng, Cathy J. Bradley, Monica F. Bryant. Cancer diagnosis and treatment in working‐age adults: Implications for employment, health insurance coverage, and financial hardship in the United States . CA: A Cancer Journal for Clinicians , 2024; DOI: 10.3322/caac.21837

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Cancer patients can now be 'matched' to best treatment with DNA and lab-dish experiments

Identifying the most effective cancer treatment for a given patient from the get-go can help improve outcomes.

Despite many efforts to find better, more effective ways to treat cancer, it remains a  leading cause of death by disease  among children in the U.S.

Cancer patients are also getting younger. Cancer diagnoses among those under 50 has risen by  about 80% worldwide  over the past 30 years. As of 2023, cancer is the  second-leading cause of death  both in the U.S. and around the world. While death rates from cancer have decreased over the past few decades,  about 1 in 3 patients in the U.S.  and  1 in 2 patients worldwide  still die from cancer.

Despite advances in standard cancer treatments, many cancer patients still face uncertain outcomes when these treatments prove ineffective. Depending on the stage and location of the cancer and the patient's medical history, most cancer types are treated with a mix of radiation, surgery and drugs. But if those standard treatments fail, patients and doctors enter a trial-and-error maze where effective treatments become difficult to predict because of limited information on the patient's cancer.

My mission as a  cancer researcher  is to build a personalized guide of the most effective drugs for every cancer patient. My team and I do this by testing different medications on a patient's own cancer cells before administering treatment, tailoring therapies that are most likely to selectively kill tumors while minimizing toxic effects.

In our newly published results of the first clinical trial combining drug sensitivity testing with DNA testing to identify effective treatments in children with cancer, an approach called  functional precision medicine , we found this approach  can help match patients  with more FDA-approved treatment options and significantly improve outcomes.

What is functional precision medicine?

Even though two people with the same cancer might get the same medicine, they can have very different outcomes. Because each patient's tumor is unique, it can be challenging to know which treatment works best.

To solve this problem, doctors analyze DNA mutations in the patient's tumor, blood or saliva to match cancer medicines to patients. This approach is called  precision medicine . However, the relationship between cancer DNA and how effective medicines will be against them is very complex. Matching medications to patients based on a single mutation overlooks other genetic and nongenetic mechanisms that influence how cells respond to drugs.

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How to best match medicines to patients through DNA is still a major challenge. Overall,  only 10% of cancer patients   experience a clinical benefit  from treatments matched to tumor DNA mutations.

Functional precision medicine takes a different approach to personalizing treatments. My team and I take a sample of a patient's cancer cells from a biopsy, grow the cells in the lab and expose them to over 100 drugs approved by the Food and Drug Administration. In this process, called  drug sensitivity testing , we look for the medications that kill the cancer cells.

New clinical trial results

Providing functional precision medicine to cancer patients  in real life  is very challenging. Off-label use of drugs and financial restrictions are key barriers. The health of cancer patients can also deteriorate rapidly, and physicians may be hesitant to try new methods.

But this is starting to change. Two teams in Europe recently showed that functional precision medicine could match effective treatments to  about 55% of   adult patients  with blood cancers such as leukemia and lymphoma that did not respond to standard treatments.

Most recently, my team's clinical trial  focused on childhood cancer patients  whose cancer came back or didn't respond to treatment. We applied our functional precision medicine approach to 25 patients with different types of cancer.

Our trial showed that we could provide treatment options for almost all patients in less than two weeks. My colleague  Arlet Maria Acanda de la Rocha  was instrumental in helping return drug sensitivity data to patients as fast as possible. We were able to provide test results within 10 days of receiving a sample, compared with the roughly 30 days that standard genomic testing results that focus on identifying specific cancer mutations typically take to process.

Most importantly, our study showed that  83% of cancer patients  who received treatments guided by our approach had clinical benefit, including improved response and survival.

Expanding into the real world

Functional precision medicine opens new paths to understanding how cancer drugs can be better matched to patients. Although doctors can read any patient's DNA today, interpreting the results to understand how a patient will respond to cancer treatment is much more challenging. Combining drug sensitivity testing with DNA analysis can help personalize cancer treatments for each patient.

I, along with colleague  Noah E. Berlow , have started to add artificial intelligence to our functional precision medicine program. AI enables us to analyze each patient's data to better match them with tailored treatments and drug combinations. AI also allows us to understand the complex relationships between DNA mutations within tumors and how different treatments will affect them.

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My team and I have  started two   clinical trials  to expand the results of our previous studies on providing treatment recommendations through functional precision medicine. We're recruiting a larger cohort of adults and children with cancers that have come back or are resistant to treatment.

The more data we have, the easier it will become to understand how to best treat cancer and ultimately help more patients access personalized cancer treatments.

This edited article is republished from The Conversation under a Creative Commons license. Read the original article .

Diana Azzam is an Assistant Professor and Research Director of the newly established Center for Advancing Personalized Cancer Treatments (CAPCT) at Florida International University. She has a Masters in Biochemistry from the American University of Beirut, Lebanon and a PhD in Biochemistry & Molecular Biology from the University of Miami, Florida. Her lab focuses on implementing functional precision medicine (FPM) approaches in adult and pediatric cancer patients that have run out of treatment options. Working with local hospitals including Nicklaus Children's Hospital and Cleveland Clinic Florida, her lab delivers individualized treatment plans based on a patient's cancer genomic profile and ex vivo drug response. She is currently engaged in two clinical studies to assess feasibility and clinical utility of FPM in relapsed/refractory patients with childhood cancer (ClinicalTrials.gov registration: NCT05857969) and adult cancer (ClinicalTrials.gov registration: NCT06024603). She is working on setting up the first CLIA-certified lab in the State of Florida dedicated for functional cancer drug testing. Her goal is to launch large-scale prospective multi-center randomized clinical trials to better assess efficacy of FPM approaches in the treatment of refractory/relapsed cancers. In parallel, she is working on utilizing FPM as a tool to reduce health disparities in childhood cancer patients from minority populations. She is also integrating a novel machine learning approach to identify specific biomarkers among minority populations that can be targeted using FDA-approved drugs. Her lab also investigates cancer stem cells and how they may result from chronic environmental exposures to toxic metals such as arsenic.

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A review of cancer immunotherapy: from the past, to the present, to the future

K. esfahani.

* Departments of Medicine and Oncology, Segal Cancer Centre, Sir Mortimer B. Davis Jewish General Hospital, Rossy Cancer Network, McGill University, Montreal, QC

N. Buhlaiga

S.v. del rincon.

† Department of Oncology, Lady Davis Institute, Sir Mortimer B. Davis Jewish General Hospital, McGill University, Montreal, QC

W.H. Miller, Jr

Compared with previous standards of care (including chemotherapy, radiotherapy, and surgery), cancer immunotherapy has brought significant improvements for patients in terms of survival and quality of life. Immunotherapy has now firmly established itself as a novel pillar of cancer care, from the metastatic stage to the adjuvant and neoadjuvant settings in numerous cancer types. In this review article, we highlight how the history of cancer immunotherapy paved the way for discoveries that are now part of the standard of care. We also highlight the current pitfalls and limitations of cancer checkpoint immunotherapy and how novel research in the fields of personalized cancer vaccines, autoimmunity, the microbiome, the tumour microenvironment, and metabolomics is aiming to solve those challenges.

INTRODUCTION

The field of immuno-oncology has been transformational in the care of cancer patients. William B. Coley, now widely accepted as the father of immunotherapy, first attempted to harness the power of the immune system for treating cancer in the late 19th century. As an orthopedic surgeon who operated on patients with bone sarcomas, he noticed that some patients with significant postoperative wound infections—a common occurrence when aseptic technique had not yet been optimized—would undergo spontaneous regression of their unresected tumours. Beginning in 1891, Coley injected more than a thousand patients with mixtures of live and inactivated bacteria such as Streptococcus pyogenes and Serratia marcescens with the hope of inducing sepsis and strong immune and antitumour responses. His cocktail of bacteria became widely known as “Coley’s toxin” and represents the first documented active cancer immunotherapy intervention 1 . Coley achieved durable complete remissions in several types of malignancies, including sarcoma, lymphoma, and testicular carcinoma. However, the lack of a known mechanism of action for Coley’s toxin and the risks of deliberately infecting cancer patients with pathogenic bacteria caused oncologists to adopt surgery and radiotherapy as alternative standard treatments early in the 20th century 2 .

It would take more than half a century before a better understanding of the key mediators of sepsis would shed some light on the mechanisms of action of Coley’s toxin. Those mediators constitute a cytokine family including interleukins, interferons, and chemokines 3 . Once again, the race was on to apply those novel discoveries to cancer therapy 4 . Physicians and researchers achieved modest success with this novel approach, occasionally inducing clinical remissions with high-dose interleukin 2 ( il -2) in metastatic renal cell carcinoma 5 and debatable responses with interferon in stages iii and iv melanoma 6 . Those modest successes were often counterbalanced with significant adverse events. Although novel methods of delivery such as pegylation would abate some of the toxicities, the sporadic and unpredictable immune responses seen with those therapies meant that only a small, carefully selected subgroup of cancer patients would benefit.

The next revolutionary wave in cancer immunotherapy came with the better understanding of the process of immune surveillance, by which innate immune cells eliminate cancer cells. The recent discovery of T cell immune checkpoints, such as ctla -4 and PD-1, propelled the field of immuno-oncology into its current era and saw the awarding of the 2018 Nobel prize in Physiology or Medicine to Drs. Allison and Honjo. Those hardwired signals have the crucial task of maintaining a fine balance between immune surveillance against foreign pathogens or abnormal cells and autoimmunity. Blocking those T cell surface receptors results in enhanced autoimmunity that induces an immune response against tumours, but can also increase the chance of autoimmune reactions.

In this review article, we highlight the current standards of care in cancer immunotherapy, with a strong focus on immune checkpoint inhibitors ( ici s), their limitations and pitfalls, and promising novel approaches.

Overview of Checkpoint Inhibitors

Cancer immuno-editing is the process by which various immune system components protect the host against primary tumour development or enhance tumour escape, or both, either by sculpting tumour immunogenicity or attenuating antitumour immune responses 7 . The process is tightly regulated by immune checkpoints, which are immune-cell surface receptors controlling either the activation or the inhibition of immune responses. Activation of the immune system is, on the one hand, the desired outcome to achieve tumour control, but on the other hand, responsible for autoimmunity. The discovery and development of monoclonal antibodies against the inhibitory immune checkpoints ctla -4 and PD-1 have resulted in dramatic antitumour responses by the up-regulation of immune activation at various stages of the immune cycle.

Immune checkpoint inhibitor therapies are now widely indicated in numerous cancer types ( Table I ). Furthermore, numerous ongoing clinical trials are assessing the potential of other agonistic or inhibitory checkpoints to affect tumour-related outcomes ( Table II ). The checkpoints are not equal in their potential. For example, the agonistic OX40 antibody has modest clinical activity, but the CD28 antibody—even at very subtherapeutic doses—resulted in massive cytokine syndrome and the intensive-care hospitalization of the first 6 healthy volunteers treated 8 . In that light, finding the right combination of ici therapy to induce the optimal amount of immune activation remains an active area of clinical research.

Indications for immune checkpoint inhibitors in advanced-stage cancers, as currently approved by Health Canada a

NSCLC = non-small-cell lung cancer; RCC = renal cell carcinoma (clear cell); SCCHN = squamous-cell carcinoma of head and neck; Tx = treatment; ASCT = autologous stem-cell transplantation; CTxRT = chemoradiotherapy.

Agonistic and antagonistic immune checkpoint modulators currently under investigation

Poly-ICLC = polyinosinic-polycytidylic acid–poly–L-lysine carboxymethylcellulose.

Modulating and Predicting Immune Toxicity for Better Efficacy

Immunotherapies are often limited by their immune-related adverse events (ir ae s), an immune activation and inflammatory response against the host’s healthy tissues. Immune activation against the host’s tumour is the desired outcome, but ir ae s are challenging to predict, diagnose, and treat. In the setting of metastatic melanoma, the addition of a ctla -4 antibody to PD-1 blockade is associated with only an incremental increase in survival, but at the cost of more than double the rate of serious ir ae s 9 . A recent meta-analysis reported a fatality rate of up to 1 patient in every 77 treated using an ici combination 10 . For specific ir ae s, such as immune-related myocarditis, the mortality rate is as high as 50% in treated patients 11 . Numerous predictors of ir ae s have been proposed (baseline lymphopenia and eosinophilia, B cell changes, T cell repertoire, circulating il -17, and gut microbiota changes 12 – 17 ), but few have been prospectively validated.

For serious ir ae s, guidelines recommend broad immunosuppression consisting of corticosteroids, followed by one or more biologics (tumour necrosis factor inhibitors) or T cell suppressants (such as mycophenolate mofetil) 18 – 20 . Very little prospective knowledge has been developed about the consequences of those therapies for cancer-related outcomes. An analysis of the baseline use of corticosteroids in patients with lung cancer reported an association with worse survival outcomes 21 . Similarly, the use of high-dose steroids in the setting of immune-related hypophysitis in patients with metastatic melanoma was also associated with worse survival 22 . On the other hand, the use of corticosteroids in other clinical settings in which patients experience ir ae s was not associated with a reduced response to ici therapy or with survival 23 . More studies are needed to assess the optimal immunosuppression regimen to be used with ici s to avoid impairing their efficacy. The use of m tor (mechanistic target of rapamycin) inhibitors shows promise to abate toxicities without impairing ici efficacy in the specific setting of organ transplantation 24 – 26 .

Modulating cytokines in the setting of an ici is a dualedged sword. Many of those soluble factors, such as tumour necrosis factor α and il -17, are called “pleiotropic cytokines” for the dual roles they play in immunity: on the one hand, they promote tumour surveillance; on the other hand, they can be key mediators of autoimmune reactions. As discussed earlier, circulating il -17 is a biomarker for the prediction of ici -induced colitis 16 . The addition of the il -17 monoclonal antibody secukinumab for the treatment of immune-related colitis and psoriasis, while effective at abating immune toxicities, has been reported to induce tumour escape 27 . The same effect has not yet been reported for tumour necrosis factor α or il -6. Tumour necrosis factor blockade seems not only to be safe for the treatment of ici -related colitis, but in animal models of melanoma, also adds synergistic antitumour efficacy to PD-1 inhibition 28 , 29 . Those early observations collectively highlight the importance of further study of the role of various cytokines and immune cells in the pathogenesis of ir ae s.

A New Era for Tumour-Specific Vaccines in Combination with ICIs

Despite promising results with ici s, single-agent PD-1 inhibitor has an objective response rate that varies from almost nonexistent in pancreatic cancer and microsatellite-stable colonic adenocarcinoma, to an average of 15%–30% in most other tumour types, but 50%–80% in melanoma, Hodgkin lymphoma, squamous-cell carcinoma of the skin, and Merkel cell carcinoma. The addition of an anti– ctla -4 agent increases the response rate, but comes with a significantly higher toxicity rate. A rational approach to achieving a higher response rate without increasing autoimmunity has been to combine an ici with a therapy that can sensitize the host’s immune system to the tumour in advance. Recent studies have shown that personalized neoantigen-based tumour-specific vaccines hold considerable promise.

Unlike hematologic malignancies, in which a common antigen is uniformly expressed on the surface of all malignant cells, making them amenable to targeted therapies such as therapy with chimeric antigen receptor T cells, solid tumours either lack such an antigen or undergo mutations under natural selection when exposed to therapeutic interventions such as monoclonal antibodies. Traditional cancer vaccines have failed for a number of potential reasons, including improper selection of a target antigen, lack of immunogenicity, or inadequate patient selection. In the new era of cancer vaccines, efficacy relies on computational pipelines geared to identify personal candidate neoantigens in real time. Comprehensive mutation analysis is performed by whole-exome sequencing, and based on affinity predictions, neo-epitopes encoded by somatic mutations in the tumour are selected given their probability of being presented by the individual’s major histocompatibility class molecules 30 – 34 . One of the most commonly used prediction algorithms for major histocompatibility class i binding, NetMHCpan (DTU Health Tech, Technical University of Denmark, Kongens Lyngby, Denmark), relies on state-of-the-art neural networks, putting the spotlight on the current power of bioinformatics for guiding precision immuno-oncology 35 . The concept has been translated to multiple phase i clinical trials evaluating neoantigen-based vaccines 36 – 38 . Other clinical trials are testing this novel vaccination strategy in combination with ipilimumab ( {"type":"clinical-trial","attrs":{"text":"NCT02950766","term_id":"NCT02950766"}} NCT02950766 at https://ClinicalTrials.gov/ ) or nivolumab ( {"type":"clinical-trial","attrs":{"text":"NCT02897765","term_id":"NCT02897765"}} NCT02897765 ), or as a personalized messenger rna mutatome vaccine in combination with the PD-L1 inhibitor atezolizumab ( {"type":"clinical-trial","attrs":{"text":"NCT03289962","term_id":"NCT03289962"}} NCT03289962 ).

The Crucial Role of the Tumour Microenvironment

An important advance in the field of immuno-oncology came from the increased understanding of the crucial role of the tumour microenvironment in the modulation of anticancer immune responses. In colorectal cancers, immune cell infiltration into the tumour microenvironment has been correlated with a strong immune response to treatment with ici s, with even better correlation than for microsatellite instability 39 , 40 . Based on those findings, the concept of “immune contexture” has been proposed and validated, with tumours classified into four proposed categories (hot, excluded, immunosuppressed, and cold) 41 , 42 . Apart from the presence of tumour-infiltrating lymphocytes, additional features such as the expression of anti–PD-L1 on tumour-associated immune cells, genomic instability, and the presence of a pre-existing antitumour immune response have been described as characteristics of “hot” tumours, which are associated with a good response to ici s 43 . Conversely, apart from being poorly infiltrated, “cold” tumours have also been described to be immunologically “ignorant” (scarcely expressing PD-L1) and characterized by high proliferation with a low mutational burden (low expression of neoantigens) and by low expression of antigen presentation machinery markers such as major histocompatibility class i 43 . Transforming “cold” tumours into fertile “hot” tumours responsive to ici s is an active area of investigation.

Radiotherapy and chemotherapy have both been used in combination with ici s to increase the antigenicity and priming potential of tumours, which in turn could be applied to turn “cold” tumours into “hot” ones. Ionizing radiation–induced immunogenic cell death and antigen release could potentially turn tumour cells into an in situ vaccine 44 . The outcome of that approach is not only local tumour control, but possibly a response at distant tumour sites through the abscopal effect 45 . On the other hand, chemotherapy can induce mutations, leading to the generation of neo-epitopes and therefore increasing the antigenicity of tumours 46 . Other approaches with proven benefit have been the local injection of oncolytic viruses into tumour beds. These native or genetically modified viruses selectively infect and replicate within tumour cells, eventually leading to tumour cell lysis and antigen release 47 . Again, that process results in local priming of the immune system, with responses seen both locally and systemically. The effect is accentuated when those therapies are combined with ici s 48 .

Another key targetable characteristic of “cold” tumours is strong expression of mesenchymal and collagen barrier molecules that prevent the migration of tumour-infiltrating lymphocytes to the tumour bed 49 , 50 . As an example, inhibition of transforming growth factor β, a key player in the formation of the mesenchymal barrier, when combined with an ici resulted in a strong antitumour response in mouse models 51 . That approach is now being tested in clinical trials.

Finally, another strategy that can convert a “cold” to a “hot” tumour microenvironment uses inhibitors of oncogenic kinases (reviewed in Guo et al. 52 ). The pi 3 k / akt pathway, glycogen synthase kinase 3α/β, and Mnk1 and Mnk2 are often aberrantly activated in cancer, and appreciation for their tumour-extrinsic effects in the cells of the tumour microenvironment to promote immune suppression is growing. For example, Mnk1 and Mnk2, which are critical regulators of messenger rna translation, have important immunomodulatory antitumor effects. Inhibitors of Mnk1 and Mnk2 can block the expression of secreted factors such as Nodal and Angptl4 53 , 54 , inhibiting the survival of neutrophils 55 and suppressing the expression of PD-L1 56 . The Mnk1 and Mnk2 inhibitors are actively being pursued in the clinic (see {"type":"clinical-trial","attrs":{"text":"NCT04261218","term_id":"NCT04261218"}} NCT04261218 , {"type":"clinical-trial","attrs":{"text":"NCT03616834","term_id":"NCT03616834"}} NCT03616834 , and {"type":"clinical-trial","attrs":{"text":"NCT03258398","term_id":"NCT03258398"}} NCT03258398 at https://ClinicalTrials.gov/ ).

Targeting Tumour Metabolism in the Tumour Microenvironment

There is growing evidence that the tumour microenvironment supports inappropriate metabolic reprogramming, negatively affecting T cell function and resulting in attenuated antitumour immune responses 57 , 58 . In that context, targeting both tumour and T cell metabolism can beneficially enhance immunity in an inhospitable microenvironment and markedly improve the success of immunotherapies. As discussed earlier, til s in the tumour microenvironment have significant prognostic and predictive significance. Their function is limited not only by immune checkpoints, but also by increasingly recognized “metabolic checkpoints” 59 .

Rapidly dividing tumour cells show complex and dynamic metabolic reprogramming and high glycolytic activity, a phenomenon called the “Warburg effect,” which is recognized as one of the hallmarks of carcinogenesis 60 . Thus, tumour cells impede the access of T cells to nutrients necessary for their activation and generate high levels of lactate. The resulting scarcity of nutrients and accumulation of metabolic waste products in the tumour microenvironment lead to a til metabolic switch that impairs optimal proliferation and function 61 .

Recent evidence suggests that ici s might directly sculpt the metabolic landscape in the tumour microenvironment, thus affecting the functioning of effector T cells. On the one hand, ctla -4 and PD-1 binding to their respective ligands impairs the metabolic til phenotype by inhibiting glycolysis 62 , thus causing reduced cytokine secretion and leading to an exhausted effector T cell phenotype 63 . On the other hand, ici s also have the opposite effect on metabolic reprogramming of cancer cells. Ligation of PD-L1 directly upregulates glycolysis in cancer cells by promoting glucose uptake and production of lactate, thus promoting tumour growth and metastasis 64 , 65 . Many therapeutic strategies have been proposed to tackle that imbalance.

The pi 3 k / akt /m tor pathway is well known to play a critical role in integrating the metabolism signals of cancer and immune cells. Recent preclinical evidence suggests that rapamycin, in combination with ici s, augments cytotoxic and memory T cell function 24 , 66 . Another promising therapeutic is metformin in combination with ici s. Metformin is known to target the mitochondrial respiratory complex i and to activate ampk pathway signal transduction, a key pathway in T cell regulatory and metabolic functioning 67 , 68 . In a cohort of patients with metastatic melanoma who received metformin in combination with ici s, favourable treatment-related outcomes (objective response rate, disease control rate, median progression-free survival, and median overall survival) were observed 69 . Those findings await further validation in larger randomized studies.

Besides glycolysis, another key element of metabolism dictating immune function in the tumour microenvironment is amino-acid catabolism. It is well established that l -arginine, tryptophan (Trp), and glutamine play fundamental roles in tumour progression and immunity 70 . Targeting those amino acids and their metabolic pathways in cancer therapy therefore becomes a promising strategy for the development of novel therapeutic agents. As one example, the depletion of tryptophan and the increase in kynurenine (Kyn) exert an important immunosuppressive function by activating T regulatory cells and suppressing the functioning of effector T cells 71 . The catabolic ido 1 enzyme in the Trp–Kyn–AhR metabolic pathway thus became an interesting therapeutic target. Despite promising results in early-phase clinical trials in a range of tumour types, a phase iii study of the ido 1-selective inhibitor epacadostat in combination with pembrolizumab in metastatic melanoma showed no difference between the epacadostat–pembrolizumab group and the placebo–pembrolizumab group 72 . That resulted in a diminution of interest in ido 1 inhibitors; however, other approaches to inhibiting that pathway continue to be considered. Novel Trp–Kyn–AhR pathway inhibitors such as Kyn-degrading enzymes, direct AhR antagonists, and Trp mimetics are advancing in early-stage or preclinical development 73 . Despite the uncertainty surrounding ido 1 inhibition, ample preclinical evidence supports the continued development of Trp–Kyn–AhR pathway inhibitors to enhance ici efficacy.

The Microbiome As a Master Regulator of Both ICI Efficacy and Toxicity

The host microbiome plays an important role in the efficacy of vaccine immune responses 74 , the promotion of carcinogenesis 75 – 81 , and the efficacy and toxicity of anticancer treatments 82 – 84 , including ici s 82 , 85 . A foundational study in mice showed that manipulation of the baseline flora of the gut microbiome affects melanoma growth kinetics and can enhance ici efficacy 86 . Other preclinical studies showed that the efficacy of anti– ctla -4 therapy can be compromised by antibiotic-induced dysbiosis or use of germ-free mice 87 . The efficacy of the ici could be restored in antibiotic-treated mice after gavage with Bacteroides fragilis or Bacteroides thetaiotaomicron (order Burkholderiales), or both, through an enhanced il -12–dependent type 1 T helper immune response 87 . Furthermore, analysis of stool from patients with ipilimumab-treated melanoma demonstrated selective enrichment of B. fragilis in clinical responders, possibly suggesting the presence of a ctla -4 blockade–induced gut dysbiosis.

Other key studies have focused on identifying human microbiota signatures predictive of clinical ici responses 88 – 92 . Patients with metastatic melanoma who were responders to anti–PD-1 therapy were shown to have enrichment of Bifidobacterium longum, Collinsella aerofaciens , and Enterococcus faecium in pre-treatment stool samples 89 . Subsequent fecal microbiota transplantation ( fmt ) of “responder” gut flora into germ-free mice was associated with improved melanoma tumour control through a CD8+ T cell immune response 89 . Furthermore, the ratio of “beneficial” to “non-beneficial” bacteria species in patients was the best predictor of an antitumour clinical response 89 . Another group identified enrichment of Akkermansia muciniphila in the microbiota of responders to anti–PD-1 or PD-L1 ici s in 3 cancer subtypes. They further demonstrated that oral supplementation with A. muciniphila, Alistipes indistinctus , or Enterococcus hirae could restore ici antitumour efficacy in germ-free mice colonized with bacterial species from non-responder fmt 88 . A third fundamental study showed that patients with melanoma responding to ici had greater alpha diversity in their gut flora, with selective enrichment in order Clostridiales family Ruminococcaceae , especially genus Faecalibacterium 90 . On the other hand, the microbiomes in ici non-responders showed a shift toward order Bacteroidales. Taken together, those studies demonstrate that the antitumour immune response depends on the composition of the gut microbiome and that antibiotic-induced dysbiosis is associated with reduced immune priming and primary resistance to immunotherapy. The deleterious effect of antibiotics given close to the time of ici treatment was confirmed in retrospective analyses of ici -treated patients with various cancers (renal cancer, non-small-cell lung cancer, urothelial cancer, and melanoma) 88 , 93 – 95 . Thus far, a modest overlap in key microbiome mediators of response to anti–PD-1 or PD-L1 therapies has been observed across cohorts, with an apparent common responder signature enriched in A. muciniphila , Clostridiales, E. faecium, Eubacterium species, the Firmicutes, and Ruminococcus species 96 . Although poor overlap between study cohorts might be a result of differences in technique or tumour type, additional heterogeneity of the gut microbiome linked to genetics, geography, lifestyle, or prior antibiotic and other drug exposure must be considered. Ultimately, “responder” gut profiles will likely reflect combinations of taxonomic orders and families rather than the presence or absence of one or a few particular species.

Besides priming the immune response to ici s, the microbiome also modulates ir ae s 17 , 91 . For instance, metagenomic sequencing found members of the Bacteroidetes phylum (families Bacteroidaceae, Rikenellaceae , and Barnesiellaceae) to be more abundant in stools obtained before treatment from patients with melanoma who did not develop ipilimumab-induced colitis, implying a protective effect of those microorganisms 17 . Importantly, specific microbial metabolic pathways (polyamine transport and vitamin B synthesis) were found to be predictive of resistance to ctla -4 blockade–induced colitis 17 . Another group corroborated the protective effect of a Bacteroidetes-rich phylotype against ctla -4 blockade–induced colitis in patients with melanoma. They further demonstrated that favourable clinical responses and susceptibility to colitis were both correlated with baseline microbiota enrichment in phylum Firmicutes (unclassified Ruminococcaceae, Clostridium cluster XIVa, and Blautia) and, in particular, Faecalibacterium , which is known to exert an anti-inflammatory role in the gut 91 . Further, the resolution of refractory ici -associated colitis in 2 patients with cancer was achieved by fmt from a healthy donor 97 . Thus, a critical goal of microbiome manipulation is to disentangle the modulation of toxicity from the preservation or enhancement of ici efficacy 98 .

There is a strong push to translate those newly acquired basic science findings about the microbiota into therapeutic clinical tools. Several trials are evaluating safety, efficacy, and immune profile changes in patients with ici -resistant cancer treated with “complete responder” fmt (see {"type":"clinical-trial","attrs":{"text":"NCT03353402","term_id":"NCT03353402"}} NCT03353402 , {"type":"clinical-trial","attrs":{"text":"NCT03341143","term_id":"NCT03341143"}} NCT03341143 , and {"type":"clinical-trial","attrs":{"text":"NCT03637803","term_id":"NCT03637803"}} NCT03637803 at https://ClinicalTrials.gov/ ). The safety of fmt is particularly important and under scrutiny, given that fmt or bacterial colonization experiments in mice have revealed a potential for transfer of chronic diseases 99 , 100 or increased risk of tumorigenesis 76 , 101 . Probiotics—loosely defined as health-promoting live organisms or fermented foods—are so far being assessed mostly in clinical trials aiming to reduce anticancer treatment toxicities; only one registered trial is testing their efficacy in the context of ici s ( {"type":"clinical-trial","attrs":{"text":"NCT03829111","term_id":"NCT03829111"}} NCT03829111 ). The optimal probiotic cocktail for immunotherapy remains to be determined and might vary with the ici or the tumour type. Additionally, reliable preparation of probiotics will be essential, likely requiring changes to their regulation. Ultimately, clinical studies of the effects of the microbiome on ici efficacy or toxicity will have to consider other confounding factors known to affect the commensal microbiome, such as concomitant radiation therapy 102 , exposure to antibiotics or other drugs (proton-pump inhibitors, antipsychotics, antimetabolites) 103 , and diet (including method and composition).

Cancer immunotherapy has dramatically changed survival and quality of life for patients. However, not all cancers are equal, and very few predictors of response and toxicity currently exist. Despite the rapid advances made in the field, immuno-oncology is still in its relative infancy, with numerous challenges and hurdles yet to be overcome. Over time, a realization grew that the standard tools used to assess choice of treatments in the era of chemotherapy and targeted therapies might not be valid for the new immunotherapies. As an example, the Response Evaluation Criteria in Solid Tumors ( recist ) used to assess response to treatments were modified to create i recist , which accounts for the novel patterns of response seen during immunotherapy, including tumour pseudoprogression 104 . In the same way that TNM staging has been crucial in guiding treatments in the era of chemotherapy, novel tools are required in the era of cancer immunotherapy. The Immunoscore has already been validated as adding important prognostic information to TNM staging in colon cancer 39 . The fact that T cells are currently widely recognized as the key mediators of antitumour efficacy with ici treatment suggests that use of the Immunoscore is an attractive option to help guide treatment selection in other cancer types as well. Still, that option does not exclude the possible use of additional parameters that might provide further insights into the specifics of each case.

It is becoming more challenging to increase the efficacy of combination therapies already established in clinical practice. In metastatic melanoma, combined ctla -4 and PD-1 blockade has achieved an unprecedented five-year overall survival above 50% 105 . In metastatic renal cell carcinoma, the same combination has been associated with an overall survival rate exceeding 60% at 3 years in the intention-to-treat population 106 , 107 . In the large landscape of ongoing early-phase clinical trials, few novel combinations have achieved a level of efficacy rivalling those new standards of care. What certainly remains to be improved is their safety profiles.

The approved induction and regimen dose of combination ici s (ipilimumab 3 mg/kg and nivolumab 1 mg/kg every 3 weeks) in the setting of melanoma is associated with a 59% rate of grades 3–4 toxicities 108 . Preliminary results from CheckMate 511, which used alternative dosing (ipilimumab 1 mg/kg and nivolumab 3 mg/kg every 3 weeks), showed a significant improvement in toxicity without loss of efficacy 109 . Given that ir ae s can sometimes be associated with mortality and significant lifelong morbidity (for example, de novo insulin-dependent diabetes, persistent pituitary dysfunction, or immune-related inflammatory arthropathies), predictors and novel strategies to abate those toxicities are urgently needed.

Another area of urgent need is to find novel treatments both for patients who are primary non-responders to ici s and for those who develop secondary resistance to those therapies. Beyond ici failure, very few treatments have been studied, and physicians often rely on previously validated standards of care for each specific cancer. Early observational data suggest that exposure to ici s might modulate the response to standard treatments received after progression. For instance, exceptionally high response rates to chemotherapy have occasionally been documented after ici failure 110 , 111 . Those observations might be secondary to immunotherapy having removed the inhibition initially exerted by tumour cells or other immune cells, followed by cytotoxic chemotherapy–mediated killing of tumour cells. On the other hand, progression-free survival and the adverse event profiles associated with exposure to targeted therapies (such as braf inhibition in melanoma) might be adversely affected by first-line exposure to ici s 112 .

To summarize, the future of cancer immunotherapy could rely on combination therapies using checkpoint inhibitors not with other novel checkpoint inhibitors, but rather with personalized cancer vaccines and novel targeted therapies directed at the tumour microenvironment, tumour glycosylation, and the host microbiome, as outlined in the present review. Advances in those fields will allow movement away from the current broad “shotgun” approach, which exposes all comers within the approved indications to ici s, to treatments tailored to the factors that make each cancer and host a unique pairing.

CONFLICT OF INTEREST DISCLOSURES

We have read and understood Current Oncology’ s policy on disclosing conflicts of interest, and we declare the following interests: WHM reports personal fees from Bristol–Myers Squibb, Merck, Roche, Novartis, and Amgen outside the submitted work; and KE reports personal fees from Bristol–Myers Squibb outside the submitted work. LR and NB have no conflicts of interest to disclose.