PH-Binding Motif in PAR4 Oncogene: From Molecular Mechanism to Drug Design.

While the role of G-protein-coupled receptors (GPCR) in cancer is acknowledged, their underlying signaling pathways are understudied. Protease-activated receptors (PAR), a subgroup of GPCRs, form a family of four members (PAR1-4) centrally involved in epithelial malignancies. PAR4 emerges as a potent oncogene, capable of inducing tumor generation. Here, we demonstrate identification of a pleckstrin-homology (PH)-binding motif within PAR4, critical for colon cancer growth. In addition to PH-Akt/PKB association, other PH-containing signal proteins such as Gab1 and Sos1 also associate with PAR4. Point mutations are in the C-tail of PAR4 PH-binding domain; F347 L and D349A, but not E346A, abrogate these associations. Pc(4-4), a lead backbone cyclic peptide, was selected out of a mini-library, directed toward PAR2&4 PH-binding motifs. It effectively attenuates PAR2&4-Akt/PKB associations; PAR4 instigated Matrigel invasion and migration in vitro and tumor development in vivo. EGFR/erbB is among the most prominent cancer targets. AYPGKF peptide ligand activation of PAR4 induces EGF receptor (EGFR) Tyr-phosphorylation, effectively inhibited by Pc(4-4). The presence of PAR2 and PAR4 in biopsies of aggressive breast and colon cancer tissue specimens is demonstrated. We propose that Pc(4-4) may serve as a powerful drug not only toward PAR-expressing tumors but also for treating EGFR/erbB-expressing tumors in cases of resistance to traditional therapies. Overall, our studies are expected to allocate new targets for cancer therapy. Pc(4-4) may become a promising candidate for future therapeutic cancer treatment.

[THE LIQUID BIOPSY REVOLUTION IN BREAST CANCER - APPLICATIONS AND POSSIBILITIES].

INTRODUCTION: Over the past two decades there have been significant developments in the fields of laboratory technology, genetics and bioinformatics. These developments have raised the attractiveness of liquid biopsy - a test aimed to detect tumor markers in body fluids. One of the liquid biopsy methods is based on identification of circulating tumor DNA - fragments of DNA originating from the tumor which are evident in the bloodstream - revealing the various tumor characteristics via simple blood tests. This novel approach has several advantages over the traditional biopsy: it is noninvasive and thus more convenient and safer for the patient; it reflects the characteristics of the entire tumor tissue present in the patient's body in a single test; it is performed quickly and safely by a phlebotomist and does not rely on the subjective interpretation of the pathologist. The liquid biopsy is a highly valuable tool for the diagnosis and monitoring of cancer, which can be recruited for the clinical management of breast cancer - the most common malignancy in females which is estimated to affect one in every eight women. In this review we will present the existing and the potential applications of the liquid biopsy in breast cancer patients, regarding the various settings of patient care - diagnosis, treatment and follow-up.

Potential Refinement of Recurrence Score by pSTAT3 Status.

The likelihood of recurrence in breast cancer patients with hormone receptor-positive (HR-positive) tumors is influenced by clinical, histopathological, and molecular features. Recent studies suggested that activated STAT3 (pSTAT3) might serve as a biomarker of outcome in breast cancer patients. In the present work, we have analyzed the added value of pSTAT3 to OncotypeDx Recurrence Score (RS) in patient prognostication. We have found that patients with low RS (<26) and low pSTAT3 might represent a population at a higher risk for cancer recurrence. Furthermore, we have observed that a positive pSTAT3 score alone can be a favorable marker for patients with HR-positive breast cancer under the age of 50. In an era of personalized medicine, these findings warrant further appraisal of chemotherapy benefit in this population.

Author Correction: Clinical Implications of Sub-grouping HER2 Positive Tumors by Amplicon Structure and Co-amplified Genes.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Clinical Implications of Sub-grouping HER2 Positive Tumors by Amplicon Structure and Co-amplified Genes.

ERBB2 amplification is a prognostic marker for aggressive tumors and a predictive marker for prolonged survival following treatment with HER2 inhibitors. We attempt to sub-group HER2+ tumors based on amplicon structures and co-amplified genes. We examined five HER2+ cell lines, three HER2+ xenographs and 57 HER2+ tumor tissues. ERBB2 amplification was analyzed using digital droplet PCR and low coverage whole genome sequencing. In some HER2+ tumors PPM1D, that encodes WIP1, is co-amplified. Cell lines were treated with HER2 and WIP1 inhibitors. We find that inverted duplication is the amplicon structure in the majority of HER2+ tumors. In patients suffering from an early stage disease the ERBB2 amplicon is composed of a single segment while in patients suffering from advanced cancer the amplicon is composed of several different segments. We find robust WIP1 inhibition in some HER2+ PPM1D amplified cell lines. Sub-grouping HER2+ tumors using low coverage whole genome sequencing identifies inverted duplications as the main amplicon structure and based on the number of segments, differentiates between local and advanced tumors. In addition, we found that we could determine if a tumor is a recurrent tumor or second primary tumor and identify co-amplified oncogenes that may serve as targets for therapy.

Ten-year clinical outcomes in N0 ER+ breast cancer patients with Recurrence Score-guided therapy.

The 21-gene Recurrence Score (RS) assay is a validated prognosticator/predictor of chemotherapy (CT) benefit in early-stage estrogen receptor (ER)-positive breast cancer (BC). Long-term data from real-life clinical practice where treatment was guided by the RS result are lacking. We performed exploratory analysis of the Clalit Health Services (CHS) registry, which included all CHS patients with node-negative ER+ HER2-negative BC who underwent RS testing between 1/2006 and 12/2009 to determine 10-year Kaplan-Meier estimates for distant recurrence/BC-specific mortality (BCSM) in this cohort. The analysis included 1365 patients. Distribution of RS results: RS 0-10, 17.8%; RS 11-25, 62.5%; RS 26-100, 19.7%. Corresponding CT use: 0, 9.4, and 69.9%. Ten-year distant recurrence rates in patients with RS 0-10, 11-25, and 26-100: 2.6% (95% confidence interval [CI], 1.1-6.2%), 6.1% (95% CI, 4.4-8.6%), and 13.1% (95% CI, 9.4-18.3%), respectively (P < 0.001); corresponding BCSM rates: 0.7% (95% CI 0.1-5.1%), 2.2% (95% CI, 1.3-3.7%), and 9.5% (95% CI, 6.0-14.9%) (P < 0.001). When the analysis included patients treated with endocrine therapy alone (95.5/87.5% of patients with RS 0-10/11-25), 10-year distant recurrence and BCSM rates for RS 0-10 patients were 2.7% (95% CI, 1.1-6.5%) and 0.8% (95% CI, 0.1-5.3%), respectively, and for RS 11-25 patients, 5.7% (95% CI, 3.9-8.3%) and 2.0% (95% CI, 1.1-3.7%), respectively. For RS 11-25 patients, no statistically significant differences were observed in 10-year distant recurrence/BCSM rates between CT-treated and untreated patients; however, this should be interpreted cautiously since the number of events was low and patients were not randomized. In conclusion, in node-negative ER+ HER2-negative BC patients, where treatment decisions in real-life clinical practice incorporated the RS, patients with RS 0-25 (~80% of patients, <10% CT use) had excellent outcomes at 10 years. Patients with RS 26-100 had high distant recurrence risk despite CT use and are candidates for new treatment approaches.

Autoimmunity and Benefit from Trastuzumab Treatment in Breast Cancer: Results from the HERA Trial.

BACKGROUND/AIM: This study sought to determine whether an autoimmune background could identify patients with HER2-positive early breast cancer (EBC) who derive differential benefit from primary adjuvant trastuzumab-based therapy. PATIENTS AND METHODS: HERA is an international randomized trial of 5,102 women with HER2-positive EBC, who were enrolled to either receive adjuvant trastuzumab or not. In this exploratory analysis, the interaction between autoimmune history and the magnitude of trastuzumab benefit was evaluated. RESULTS: A total of 5,099 patients were included in the current analysis. Among them, 325 patients (6.4%) had autoimmune disease history, 295 of whom had active disease. Patients were randomly assigned to trastuzumab or no-trastuzumab groups. Similar reductions in the risk of events in patients with and without autoimmune history were observed (interaction p=0.95 for disease-free survival, and p=0.62 for overall survival). CONCLUSION: No evidence of a differential benefit from trastuzumab in patients with a medical history of autoimmune disease was found.

Thyroidectomy Practice After Implementation of the 2015 American Thyroid Association Guidelines on Surgical Options for Patients With Well-Differentiated Thyroid Carcinoma.

IMPORTANCE: The recommended extent of surgery for well-differentiated thyroid carcinoma has been modified considerably in the updated 2015 American Thyroid Association guidelines published in January 2016. To date, the changes in clinical practice after publication of these new guidelines have not been demonstrated. OBJECTIVE: The aim of this study was to evaluate clinical practice changes associated with implementation of the updated guidelines on the surgical procedure rates of total thyroidectomy, thyroid lobectomy, and completion thyroidectomy at a single tertiary medical center. DESIGN, SETTING, AND PARTICIPANTS: This is a retrospective cohort study of 169 patients at the Hadassah-Hebrew University Medical Center, Jerusalem, Israel. Patients with pathologically proved, well-differentiated thyroid carcinoma who underwent surgery between January 1, 2013, and December 31, 2014, were compared with patients who underwent surgery from January 1 to December 31, 2016. A total of 434 thyroidectomy procedures were performed during the study period, and 251 had pathologically proved, well-differentiated thyroid carcinoma. Patients with tumors larger than 4 cm, involved lymph nodes, or bilateral nodules were excluded. MAIN OUTCOMES AND MEASURES: Primary outcomes were the rate of up-front total thyroidectomy vs lobectomy and the rates of completion thyroidectomy before and after the implementation of the new guidelines. RESULTS: Of the 169 patients in the final analysis, 118 (69.8%) were included from 2013 to 2014 and 51 (30.2%) in 2016. The mean (SD) age for the entire cohort was 44 (13.8) years, and 129 (76.3%) were women. Up-front total thyroidectomy was performed in 72 of 118 patients (61.0%) prior to the 2015 American Thyroid Association guidelines and 16 of 51 (31.4%) following their implementation (odds ratio, 0.29; 95% CI, 0.14-0.59). The rate of completion thyroidectomy also significantly decreased between these periods (73.9% vs 20.0%; odds ratio, 0.09; 95% CI, 0.04-0.19). CONCLUSIONS AND RELEVANCE: The updated 2015 American Thyroid Association guidelines implementation was associated with a significant decrease in the rates of both up-front total thyroidectomy and completion thyroidectomy. According to these findings, only 1 of 5 patients who undergoes thyroid lobectomy will require a completion procedure.

Breast cancer among older women: The influence of age and cancer stage on survival.

PURPOSE OF STUDY: To describe the association between increasing age and survival among women aged over 65 years, diagnosed with breast cancer. MATERIALS AND METHODS: A historical prospective cohort study, comparing 3270 breast cancer patients to 13,163 non cancer age matched controls. Baseline characteristics and cancer data gathered from the Israeli Central Bureau of Statistics (1995), the Israel Cancer Registry (2000-2010). Baseline measurements included age, socioeconomic status. Cancer stage at diagnosis was clustered as stage I, stage II-III and metastatic. Cox Proportional Hazards regression models were used to determine Hazards Ratios (HR) for mortality. RESULTS: Between ages 65-69 and ≥85, metastatic disease rose from 3.9% to 23.4% and stage I disease declined from 58.6% to 30.1%. At age 80-84, 50% life expectancy among controls, stage I, and stage II-III disease was 95,92 and 90 months respectively, compared to 2 months for metastatic disease. Compared to controls, between the age 65-69 to ≥85, adjusted HR's progressively decreased among subjects with stage I from HR 0.96 (95% CI 0.69-1.33) to 0.60 (95%CI 0.36-1.01), stage II-III from HR 3.26 (95%CI2.58-4.12) to HR 1.60 (95%CI 1.22-2.09), and metastatic disease from HR 57.40 (95%CI 39.56-83.29) to HR 20.76 (95%CI 14.73-29.24). CONCLUSIONS: This study describes the increasingly poor prognosis and short life expectancy observed among women aged ≥80 diagnosed with metastatic breast. In contrast, our findings confirm the positive prognosis associated with rising age, among older women presenting with stage I breast cancer, among whom survival was similar, if not slightly better, than non-cancer age matched controls.

Correction to: Cancer driver G-protein coupled receptor (GPCR) induced ß-catenin nuclear localization: the transcriptional junction.

The original version of this article unfortunately contained a mistake. The family name of Beatrice Uziely was mistakenly spelled as Uzieky. The correct name is now presented above.

Cancer driver G-protein coupled receptor (GPCR) induced ß-catenin nuclear localization: the transcriptional junction.

G protein-coupled receptors (GPCRs) comprise the main signal-transmitting components in the cell membrane. Over the past several years, biochemical and structural analyses have immensely enhanced our knowledge of GPCR involvement in health and disease states. The present review focuses on GPCRs that are cancer drivers, involved in tumor growth and development. Our aim is to highlight the involvement of stabilized ß-catenin molecular machinery with a specific array of GPCRs. We discuss recent advances in understanding the molecular path leading to ß-catenin nuclear localization and transcriptional activity and their implications for future cancer therapy research.

The oncology nurse coordinator: role perceptions of staff members and nurse coordinators.

BACKGROUND: There is extensive evidence that the role of nurse coordinators is beneficial for patients. Nurse coordinators are more available to patients compared to general registered nurses, know better to control symptoms and work as team players with multiple care providers. Despite its significance, there is a dearth of literature on the subject in Israel and a lack of clarity regarding the definitions of the role in terms of responsibilities and authorities. The aim of the study is to: To examine how the role of nurse oncology coordinator is implemented in various fields of oncology and to describe the actual performance of different kinds of oncology nurse coordinators and staff perceptions regarding this role in one tertiary hospital in Jerusalem. METHODS: A phenomenological approach was used to explore the participants' experiences and views of nurse coordinators' performance. We conducted a qualitative study using in-depth semi-structured interviews. Interviewees included 30 employees from different levels of the hospitals, and leading figures associated with oncology medicine outside of the hospital: Nurses and physicians of the Sharett Oncology Institute of Hadassah Ein Kerem Hospital in Jerusalem, the administrative staff of Hadassah Ein Kerem Hospital, head nurses of the Israel Cancer Association, the chairperson of the Non-Profit Organization of Oncology Nurses, nurse directors at the Ministry of Health Nursing Division, and seven nurse coordinators at Hadassah Ein Kerem Hospital in diverse fields of oncology. RESULTS: The nurse coordinator is perceived as an important staff member providing care to cancer patients. Several key elements were found to be common features in the work of all nurse coordinators: emotional support, guidance to patients, and coordination of patients' care. CONCLUSIONS: The nurse coordinator plays a noteworthy role in the health care system. In view of the variety of roles that the nurse coordinator assumes in different units, performance standards must be adapted to the performance areas for each unit, as well as nurses' professional development requirements. Changes in a service organization and careful attention to the continuum of care highlight the need to develop and to strengthen the role of a nurse who coordinates treatment over the entire continuum of care, both in the hospital and in the community.

Clinical outcomes in patients with node-negative breast cancer treated based on the recurrence score results: evidence from a large prospectively designed registry.

The 21-gene Recurrence Score® (RS) assay is a validated prognostic/predictive tool in ER + early-stage breast cancer. However, clinical outcome data from prospective studies in RS ≥ 11 patients are lacking, as are relevant real-life clinical practice data. In this retrospective analysis of a prospectively designed registry, we evaluated treatments/clinical outcomes in patients undergoing RS-testing through Clalit Health Services. The analysis included N0 ER + HER2-negative breast cancer patients who were RS-tested from 1/2006 through 12/2010. Medical records were reviewed to verify treatments/recurrences/survival. The cohort included 1801 patients (median follow-up, 6.2 years). Median age was 60 years, 50.4% were grade 2 and 81.1% had invasive ductal carcinoma; 48.9% had RS < 18, 40.7% RS 18-30, and 10.4% RS ≥ 31, with chemotherapy use of 1.4, 23.7, and 87.2%, respectively. The 5-year Kaplan-Meier estimates for distant recurrence were 0.8, 3.0, and 8.6%, for patients with RS < 18, RS 18-30 and RS ≥ 31, respectively; the corresponding 5-year Kaplan-Meier estimates for breast cancer death were 0.0, 0.9, and 6.2%. Chemotherapy-untreated patients with RS < 11 (n = 304) and 11-25 (n = 1037) (TAILORx categorization) had 5-year Kaplan-Meier estimates for distant recurrence risk/breast cancer death of 1.0%/0.0% and 1.3%/0.4%, respectively. Our results extend those of the prospective TAILORx trial: the 5-year Kaplan-Meier estimates for distant recurrence and breast cancer death rate for the RS < 18 patients were very low supporting the use of endocrine therapy alone. Furthermore, in chemotherapy-untreated patients with RS 11-25 (where TAILORx patients were randomized to chemoendocrine or endocrine therapy alone), 5-year distant recurrence rates were also very low, suggesting that chemotherapy would not have conferred clinically meaningful benefit.

Treatment inferred from mutations identified using massive parallel sequencing leads to clinical benefit in some heavily pretreated cancer patients.

Molecular portraits of numerous tumors have flooded oncologists with vast amounts of data. In parallel, effective inhibitors of central pathways have shown great clinical benefit. Together, this promises potential clinical benefits to otherwise end-stage cancer patients. Here, we report a clinical service offering mutation detection of archived samples using the ion Ampliseq cancer panel coupled with clinical consultation.A multidisciplinary think tank consisting of oncologists, molecular-biologists, genetic counselors, and pathologists discussed 67 heavily pretreated, advanced cancer patient cases, taking into account mutations identified using ion Ampliseq cancer panel, medical history, and relevant literature.The team generated a treatment plan, targeting specific mutations, for 41 out of 64 cases. Three patients died before results were available. For 32 patients, the treating oncologists chose not to include the panel recommendation in the treatment plan for various reasons. Nine patients were treated as recommended by the panel, 5 with clinical benefit, and 4 with disease progression.This study suggests that routine use of massive parallel tumor sequencing is feasible and can judiciously affect treatment decisions when coupled with multidisciplinary team-based decision making. Administration of personalized based therapies at an earlier stage of disease, expansion of genetic alterations examined, and increased availability of targeted therapies may lead to further improvement in the clinical outcome of metastatic cancer patients.

Low-density lipoprotein receptor-related protein 6 is a novel coreceptor of protease-activated receptor-2 in the dynamics of cancer-associated ß-catenin stabilization.

Protease-activated receptor-2 (PAR2) plays a central role in cancer; however, the molecular machinery of PAR2-instigated tumors remains to be elucidated. We show that PAR2 is a potent inducer of ß-catenin stabilization, a core process in cancer biology, leading to its transcriptional activity. Novel association of low-density lipoprotein-related protein 6 (LRP6), a known coreceptor of Frizzleds (Fz), with PAR2 takes place following PAR2 activation. The association between PAR2 and LRP6 was demonstrated employing co-immunoprecipitation, bioluminescence resonance energy transfer (BRET), and confocal microscopy analysis. The association was further supported by ZDOCK protein-protein server. PAR2-LRP6 interaction promotes rapid phosphorylation of LRP6, which results in the recruitment of Axin. Confocal microscopy of PAR2-driven mammary gland tumors in vivo, as well as in vitro confirms the association between PAR2 and LRP6. Indeed, shRNA silencing of LRP6 potently inhibits PAR2-induced ß-catenin stabilization, demonstrating its critical role in the induced path. We have previously shown a novel link between protease-activated receptor-1 (PAR1) and ß-catenin stabilization, both in a transgenic (tg) mouse model with overexpression of human PAR1 (hPar1) in the mammary glands, and in cancer epithelial cell lines. Unlike in PAR1-Gα13 axis, both Gα12 and Gα13 are equally involved in PAR2-induced ß-catenin stabilization. Disheveled (DVL) is translocated to the cell nucleus through the DVL-PDZ domain. Collectively, our data demonstrate a novel PAR2-LRP6-Axin interaction as a key axis of PAR2-induced ß-catenin stabilization in cancer. This newly described axis enhances our understanding of cancer biology, and opens new avenues for future development of anti-cancer therapies.

Oncotype Dx recurrence score among BRCA1/2 germline mutation carriers with hormone receptors positive breast cancer.

Gene expression assays are widely used to predict risk of recurrence in early breast cancer (BC). We report the 21-gene expression assay (Oncotype Dx) recurrence score (RS) distribution of 27 BRCA carriers with estrogen receptor (ER) positive BCs, identified at Hadassah Medical Center, combined with 2 previous studies. Treatment decision and outcomes of the 27 BRCA carriers were compared with an Israeli cohort of 1594 patients published recently. We found Oncotype Dx RS low (<18), intermediate (18-30) and high (>30) among 12 (21.4%), 23 (41.1%) and 21 (37.5%) of 56 BRCA1 carriers compared with 15 (17.2%), 49 (56.3%) and 23 (26.4%) of 87 BRCA2 carriers (p = 0.2). The corresponding distribution in a population of 82,434 women published by Genomic Health was 53.4%, 36.3% and 10.3% for low, intermediate and high RS (p < 0.001 for BRCA1 and BRCA2). Treatment decision regarding chemotherapy according to RS was similar in BRCA1, BRCA2 and the control group. Two of 27 carriers had distant recurrence: a BRCA1 carrier with RS of 18 and a BRCA2 carrier with RS of 22; both have an excellent response to chemotherapy. We found an approximately ∼3 fold increased rate of high RS among BRCA1 and 2 carriers with ER positive BC compared with the general BC population. These data might indicate that hormone positive BC in BRCA carriers are molecularly unique. The surprisingly good response to chemotherapy in the metastatic setting in 2 patients may suggest that the predictive value of low-intermediate RS in carriers merits further studies.

Unemployment risk 2 years and 4 years following gastric cancer diagnosis: a population-based study.

PURPOSE: The needs of gastric cancer survivors have received limited attention. Returning to work after gastric cancer has not yet been described in a population-based study. We aimed to examine the unemployment risk at 2 and 4 years after gastric cancer. METHODS: The present historical prospective cohort study included baseline measurements from the Israeli Central Bureau of Statistics 1995 National Census, with follow-up until 2011. A group with gastric cancer and an age-, sex-, and ethnicity-matched control group were sampled from the census population. Binary logistic regression analyses were used to assess odds ratios (ORs) for the study outcomes, controlling for socioeconomic factors, and employment status at 2 years before diagnosis. RESULTS: Data for 152 gastric cancer cases and 464 matched controls were analyzed. Those who died during the study period were excluded. Two years after diagnosis, 53.3 % of gastric cancer survivors and 43.8 % of controls were unemployed (p = 0.04); 4 years after diagnosis, 53.9 % of survivors, and 47.2 % of controls were unemployed (p = 0.15). In the adjusted models, gastric cancer was only associated with unemployment 2 years after diagnosis (OR = 1.47, 95 % confidence interval [CI] = 1.02-2.12). This association weakened and lost significance 4 years after diagnosis (OR = 1.42, 95 % CI = 0.89-2.28). Gastric cancer was not associated with decreased income at 2 (OR = 1.48, 95 % CI = 0.91-1.48) or 4 years (OR = 1.65, 95 % CI = 0.99-2.74) after diagnosis. CONCLUSIONS: Gastric cancer survivorship was associated with unemployment 2 years after diagnosis. Longer-term survivors may have the prospect of returning to work. IMPLICATIONS FOR CANCER SURVIVORS: For patients with cancer, returning to work may be an indicator for returning to a normal lifestyle after serious illness. This study highlights the need for early social support in gastric cancer survivors to promote faster recovery.

Unemployment risk at 2 and 4 years following colorectal cancer diagnosis: a population based study.

BACKGROUND: About half of colorectal patients are diagnosed less than 65 years of age and they have a relatively high cure rate. However, little is known about their employment and related risk factors. The aim of the current study was to clarify the association between colorectal cancer (CRC) and subsequent risk of being unemployed. METHODS: A historical prospective cohort study included baseline socio-demographic measurements of age, sex, ethnicity, residential socio-economic position and education from the 1995 Israeli National Census, cancer incidence between 2000 and 2007 and employment data between 1998 and 2011. Binary logistic regression analyses were used to assess odds ratios for unemployment, while controlling for socio-economic measurements and employment status at 2 years prior to diagnosis. RESULTS: The final study population included 885 colorectal patients and 2646 healthy controls. After controlling for confounders, positive associations were found between stages II (odds ratio [OR] = 1.91, 95% confidence interval [CI]: 1.31-2.76 or III (OR = 1.70, 95% CI: 1.13-2.54) and increased risk for unemployment at 2 years. At 4 years follow-up, stages I (OR = 1.56, 95% CI: 1.11-2.19), II (OR = 1.57, 95% CI: 1.09-2.26) and III (OR = 2.28, 95% CI: 1.55-3.37) were associated with increased risk for unemployment. Higher risk was seen among rectal cancer patients and among patients aged ≤50 years old at the time of cancer diagnosis. CONCLUSIONS: CRC patients are at increased long-term risk for unemployment, especially among rectal cancer and younger patients. The clinical ramifications of our findings emphasise the importance of an accurate evaluation and attention to unemployment status during the care of these patients.