Publications by authors named "Jussi Koivunen"

47 Publications

Electronic patient-reported outcomes and machine learning in predicting immune-related adverse events of immune checkpoint inhibitor therapies.

BMC Med Inform Decis Mak 2021 06 30;21(1):205. Epub 2021 Jun 30.

Department of Oncology and Radiotherapy, Oulu University Hospital and MRC Oulu, OYS, P.B. 22, 90029, Oulu, Finland.

Background: Immune-checkpoint inhibitors (ICIs) have introduced novel immune-related adverse events (irAEs), arising from various organ systems without strong timely dependency on therapy dosing. Early detection of irAEs could result in improved toxicity profile and quality of life. Symptom data collected by electronic (e) patient-reported outcomes (PRO) could be used as an input for machine learning (ML) based prediction models for the early detection of irAEs.

Methods: The utilized dataset consisted of two data sources. The first dataset consisted of 820 completed symptom questionnaires from 34 ICI treated advanced cancer patients, including 18 monitored symptoms collected using the Kaiku Health digital platform. The second dataset included prospectively collected irAE data, Common Terminology Criteria for Adverse Events (CTCAE) class, and the severity of 26 irAEs. The ML models were built using extreme gradient boosting algorithms. The first model was trained to detect the presence and the second the onset of irAEs.

Results: The model trained to predict the presence of irAEs had an excellent performance based on four metrics: accuracy score 0.97, Area Under the Curve (AUC) value 0.99, F1-score 0.94 and Matthew's correlation coefficient (MCC) 0.92. The prediction of the irAE onset was more difficult with accuracy score 0.96, AUC value 0.93, F1-score 0.66 and MCC 0.64 but the model performance was still at a good level.

Conclusion: The current study suggests that ML based prediction models, using ePRO data as an input, can predict the presence and onset of irAEs with a high accuracy, indicating that ePRO follow-up with ML algorithms could facilitate the detection of irAEs in ICI-treated cancer patients. The results should be validated with a larger dataset. Trial registration Clinical Trials Register (NCT3928938), registration date the 26th of April, 2019.
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http://dx.doi.org/10.1186/s12911-021-01564-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8243435PMC
June 2021

Purchase of prophylactic topical corticosteroids is associated with improved survival in NSCLCs treated with EGFR TKI: real-world cohort study.

Acta Oncol 2021 Jun 17:1-6. Epub 2021 Jun 17.

Department of Medical Oncology and Radiotherapy and Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.

Background: With the first- and second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), clinical benefit and rash correlate together. EGFR TKI-induced rash can be alleviated with topical corticosteroids and tetracyclines. This study investigates whether prophylaxis with topical corticosteroids is associated with improved survival among the EGFR TKI-treated non-small cell lung cancers (NSCLCs).

Material And Methods: We collected all the patients ( = 1271) who had received reimbursement for the first- or second-generation EGFR TKIs in Finland 2011-2016, had purchased TKIs, and had data available at the Finnish Cancer Registry (FCR). Survival was analyzed from the first EGFR TKI purchase to death or the end of follow-up, and patients were stratified according to the TKIs, purchases of topical corticosteroids, and their timing.

Results: A total of 270 (21%) patients had corticosteroid purchases -14 to +200 d (all), and 196 (15%) had purchased corticosteroids as prophylaxis (-14 to +14 d) from the first EGFR TKI purchase. Corticosteroid purchases were associated with improved survival in all (0.64 95% CI 0.56-0.74) and prophylactic (0.78, 95% CI 0.66-0.92) groups when compared to non-purchasers, although these results were limited to the erlotinib users only. The survival benefit of prophylactic corticosteroids among the erlotinib users remained in multivariate analysis including sex, stage, histology, and tetracycline prophylaxis (HR 0.78, 95% CI 0.64-0.95). The prophylactic use of corticosteroids was associated with a longer erlotinib treatment duration (HR 0.75, 95% CI 0.64-0.90).

Conclusions: Prophylactic topical corticosteroids may improve the survival of NSCLC patients treated with EGFR TKIs, and they should be considered as prophylaxis when initiating EGFR TKIs with a high incidence of rash.
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http://dx.doi.org/10.1080/0284186X.2021.1937309DOI Listing
June 2021

Isolated limb perfusion with melphalan as treatment for regionally advanced melanoma of the limbs: results of 60 patients treated in Finland during 2007-2018.

Melanoma Res 2021 Jun 14. Epub 2021 Jun 14.

Department of Oncology, Comprehensive Cancer Centre Department of Pathology Department of Vascular Surgery, University Hospital of Helsinki and University of Helsinki, Helsinki Department of Oncology and Radiotherapy, Fican West Cancer Center, University of Turku and Turku University Hospital, Turku Department of Oncology and Radiotherapy, Tampere University Hospital, Tampere Department of Oncology and Radiotherapy, Oulu University Hospital, MRC Oulu, Oulu KYS, Center of Oncology, Kuopio University Hospital, Kuopio, Finland.

Isolated limb perfusion (ILP) is widely accepted as treatment for recurrent melanoma limited to the limbs. The use of ILP has decreased in recent years with the introduction of potentially effective new systemic therapies. We evaluated retrospectively if ILP still may be a treatment option in locally advanced melanoma. In Finland, ILP is centralized to the Comprehensive Cancer Center of Helsinki University Hospital. We included all ILP patients treated at our hospital between 2007 and 2018. Clinical factors and treatment outcomes were retrospectively evaluated. Altogether 60 patients received ILP. Toxicity was mostly transient. The overall response rate was 77% with 35% complete responses and 42% partial responses. The median progression-free survival (PFS) was 6.1 months (range 0.6-116.5 months) and the median melanoma-specific survival (MSS) was 29.9 months (range 3.5-138.7 months). Patients with CR had superior median PFS (19.7 months, range 2.5-116.5 vs. 4.5 months, range 0.6-39.7 months, P = 0.00003) and median MSS (median MSS not reached vs. 25.9 months, range 3.5-98.7 months, P = 0.0005) compared to other responders. Younger patients (<69 years) had longer median MSS (47.2 months, range 3.5-138.7 vs. 25.9 months, range 8.4-125.4 months, P = 0.015) compared to patients over 69 years. Treatment outcomes of Finnish ILP patients were comparable to earlier studies and some long-term survivors were observed in the group of complete responders. Median PFS and OS were longer for patients achieving a CR. Treatment was well-tolerated also among older patients.
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http://dx.doi.org/10.1097/CMR.0000000000000755DOI Listing
June 2021

Systemic Blockade of Clever-1 Elicits Lymphocyte Activation Alongside Checkpoint Molecule Downregulation in Patients with Solid Tumors: Results from a Phase I/II Clinical Trial.

Clin Cancer Res 2021 Jun 2. Epub 2021 Jun 2.

MediCity Research Laboratory, University of Turku, Turku, Finland.

Purpose: Macrophages are critical in driving an immunosuppressive tumor microenvironment that counteracts the efficacy of T-cell-targeting therapies. Thus, agents able to reprogram macrophages toward a proinflammatory state hold promise as novel immunotherapies for solid cancers. Inhibition of the macrophage scavenger receptor Clever-1 has shown benefit in inducing CD8 T-cell-mediated antitumor responses in mouse models of cancer, which supports the clinical development of Clever-1-targeting antibodies for cancer treatment.

Experimental Design: In this study, we analyzed the mode of action of a humanized IgG4 anti-Clever-1 antibody, FP-1305 (bexmarilimab), both and in patients with heavily pretreated metastatic cancer ( = 30) participating in part 1 (dose-finding) of a phase I/II open-label trial (NCT03733990). We studied the Clever-1 interactome in primary human macrophages in antibody pull-down assays and utilized mass cytometry, RNA sequencing, and cytokine profiling to evaluate FP-1305-induced systemic immune activation in patients with cancer.

Results: Our pull-down assays and functional studies indicated that FP-1305 impaired multiprotein vacuolar ATPase-mediated endosomal acidification and improved the ability of macrophages to activate CD8 T-cells. In patients with cancer, FP-1305 administration led to suppression of nuclear lipid signaling pathways and a proinflammatory phenotypic switch in blood monocytes. These effects were accompanied by a significant increase and activation of peripheral T-cells with indications of antitumor responses in some patients.

Conclusions: Our results reveal a nonredundant role played by the receptor Clever-1 in suppressing adaptive immune cells in humans. We provide evidence that targeting macrophage scavenging activity can promote an immune switch, potentially leading to intratumoral proinflammatory responses in patients with metastatic cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4862DOI Listing
June 2021

Digital Monitoring and Management of Patients With Advanced or Metastatic Non-Small Cell Lung Cancer Treated With Cancer Immunotherapy and Its Impact on Quality of Clinical Care: Interview and Survey Study Among Health Care Professionals and Patients.

J Med Internet Res 2020 12 21;22(12):e18655. Epub 2020 Dec 21.

Tumor Zentrum Aarau, Hirslanden Klinik Aarau, Aarau, Switzerland.

Background: Cancer immunotherapy (CIT), as a monotherapy or in combination with chemotherapy, has been shown to extend overall survival in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). However, patients experience treatment-related symptoms that they are required to recall between hospital visits. Digital patient monitoring and management (DPMM) tools may improve clinical practice by allowing real-time symptom reporting.

Objective: This proof-of-concept pilot study assessed patient and health care professional (HCP) adoption of our DPMM tool, which was designed specifically for patients with advanced or metastatic NSCLC treated with CIT, and the tool's impact on clinical care.

Methods: Four advisory boards were assembled in order to co-develop a drug- and indication-specific CIT (CIT+) module, based on a generic CIT DPMM tool from Kaiku Health, Helsinki, Finland. A total of 45 patients treated with second-line single-agent CIT (ie, atezolizumab or otherwise) for advanced or metastatic NSCLC, as well as HCPs, whose exact number was decided by the clinics, were recruited from 10 clinics in Germany, Finland, and Switzerland between February and May 2019. All clinics were provided with the Kaiku Health generic CIT DPMM tool, including our CIT+ module. Data on user experience, overall satisfaction, and impact of the tool on clinical practice were collected using anonymized surveys-answers ranged from 1 (low agreement) to 5 (high agreement)-and HCP interviews; surveys and interviews consisted of closed-ended Likert scales and open-ended questions, respectively. The first survey was conducted after 2 months of DPMM use, and a second survey and HCP interviews were conducted at study end (ie, after ≥3 months of DPMM use); only a subgroup of HCPs from each clinic responded to the surveys and interviews. Survey data were analyzed quantitatively; interviews were recorded, transcribed verbatim, and translated into English, where applicable, for coding and qualitative thematic analysis.

Results: Among interim survey respondents (N=51: 13 [25%] nurses, 11 [22%] physicians, and 27 [53%] patients), mean rankings of the tool's seven usability attributes ranged from 3.2 to 4.4 (nurses), 3.7 to 4.5 (physicians), and 3.7 to 4.2 (patients). At the end-of-study survey (N=48: 19 [40%] nurses, 8 [17%] physicians, and 21 [44%] patients), most respondents agreed that the tool facilitated more efficient and focused discussions between patients and HCPs (nurses and patients: mean rating 4.2, SD 0.8; physicians: mean rating 4.4, SD 0.8) and allowed HCPs to tailor discussions with patients (mean rating 4.35, SD 0.65). The standalone tool was well integrated into HCP daily clinical workflow (mean rating 3.80, SD 0.75), enabled workflow optimization between physicians and nurses (mean rating 3.75, SD 0.80), and saved time by decreasing phone consultations (mean rating 3.75, SD 1.00) and patient visits (mean rating 3.45, SD 1.20). Workload was the most common challenge of tool use among respondents (12/19, 63%).

Conclusions: Our results demonstrate high user satisfaction and acceptance of DPMM tools by HCPs and patients, and highlight the improvements to clinical care in patients with advanced or metastatic NSCLC treated with CIT monotherapy. However, further integration of the tool into the clinical information technology data flow is required. Future studies or registries using our DPMM tool may provide insights into significant effects on patient quality of life or health-economic benefits.
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http://dx.doi.org/10.2196/18655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781800PMC
December 2020

Follow-Up of Cancer Patients Receiving Anti-PD-(L)1 Therapy Using an Electronic Patient-Reported Outcomes Tool (KISS): Prospective Feasibility Cohort Study.

JMIR Form Res 2020 Oct 28;4(10):e17898. Epub 2020 Oct 28.

Department of Oncology and Radiotherapy, Oulu University Hospital, Oulu, Finland.

Background: Immune checkpoint inhibitors (ICIs) have become a standard of care for various tumor types. Their unique spectrum of side effects demands continuous and long-lasting assessment of symptoms. Electronic patient-reported outcome (ePRO) follow-up has been shown to improve survival and quality of life of cancer patients treated with chemotherapy.

Objective: This study aimed to investigate whether ePRO follow-up of cancer patients treated with ICIs is feasible. The study analyzed (1) the variety of patient reported symptoms, (2) etiology of alerts, (3) symptom correlations, and (4) patient compliance.

Methods: In this prospective, one-arm, multi-institutional study, we recruited adult cancer patients whose advanced cancer was treated with anti-programmed cell death protein 1 (PD)- ligand (L)1 agents in outpatient settings. The ePRO tool consisted of a weekly questionnaire evaluating the presence of typical side effects, with an algorithm assessing the severity of the symptom according to National Cancer Institute Common Terminology Criteria for Adverse Events and an urgency algorithm sending alerts to the care team. A patient experience survey was conducted monthly. The patients were followed up to 6 months or until disease progression.

Results: A total of 889 symptom questionnaires was completed by 37 patients (lung cancer, n=15; melanoma, n=9; genitourinary cancer, n=9; head and neck cancer, n=4). Patients showed good adherence to ePRO follow-up. The most common grade 1 symptoms were fatigue (28%) and itching (13%), grade 2 symptoms were loss of appetite (12%) and nausea (12%), and grade 3-4 symptoms were cough (6%) and loss of appetite (4%). The most common reasons for alerts were loss of appetite and shortness of breath. In the treatment benefit analysis, positive correlations were seen between clinical benefit and itching as well as progressive disease and chest pain.

Conclusions: According to the results, ePRO follow-up of cancer patients receiving ICIs is feasible. ePROs capture a wide range of symptoms. Some symptoms correlate to treatment benefit, suggesting that individual prediction models could be generated.

Trial Registration: Clinical Trials Register, NCT3928938; https://clinicaltrials.gov/ct2/show/NCT03928938.
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http://dx.doi.org/10.2196/17898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7657724PMC
October 2020

Tetracyclines increase the survival of NSCLC patients treated with EGFR TKIs: a retrospective nationwide registry study.

ESMO Open 2020 10;5(5):e000864

Oncology and Radiotherapy, Pohjois-Pohjanmaan Sairaanhoitopiiri, Oulu, Finland; MRC Oulu, Oulu University, Oulu, Finland. Electronic address:

Background: With the first and second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), clinical benefit and rash correlate together. EGFR TKI-induced rash can be alleviated with tetracyclines, but it is unknown whether the use of tetracyclines can increase the survival of non-small-cell lung cancer (NSCLC) patients treated with EGFR TKIs.

Methods: We collected all the patients (n=1271) who had reimbursement for EGFR TKIs (gefitinib, erlotinib and afatinib) in Finland 2011-2016, had purchased TKIs, and had data available at nationwide cancer registry. The survival was analysed from the first EGFR TKI purchase to death or end-of follow-up, and patients were stratified according to TKIs, purchases of antibiotics, their ATC class and timing.

Results: 802 (63.1%) patients had antibiotic purchases -14 to +200 days from the first EGFR TKI purchase, 447 of these tetracyclines. 322 (25.3%) had had purchased antibiotics -14 to +14 days (prophylaxis) from the first EGFR TKI purchase, 188 of these tetracyclines. Purchase of antibiotics was associated with improved survival (HR 0.80, 95% CI 0.71 to 0.91), which limited to tetracycline purchases only (HR 0.72, 95% CI 0.64 to 0.82). The largest survival benefit was seen with the prophylactic use of tetracyclines (HR 0.74, 95% CI 0.62 to 0.88). The benefit from tetracyclines was limited to erlotinib only (HR 0.68, 95% CI 0.58 to 0.78) which was retained in multivariate analysis. Prophylactic use of tetracyclines was associated with a longer erlotinib treatment duration (HR 0.81, 95% CI 0.61 to 0.96) but not with dose reductions or treatment breaks.

Conclusions: Tetracyclines improve the survival of NSCLC patients treated with the first and second-generation EGFR TKIs and they should be considered as a prophylaxis when initiating EGFR TKIs with high incidence of rash.
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http://dx.doi.org/10.1136/esmoopen-2020-000864DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7580060PMC
October 2020

Treatment discontinuation and re-initiation of anti-PD-(L)1 agents in metastatic cancers.

J Cancer Res Clin Oncol 2020 Aug 18;146(8):2153-2160. Epub 2020 Apr 18.

Department of Oncology and Radiotherapy, Oulu University Hospital and MRC Oulu, P.B. 22, 90029, Oulu, Finland.

Introduction: Immune checkpoint inhibitors (ICIs) are approved in multiple indications for cancer care. Most of the clinical trials have not questioned shorter than until disease progression approaches. In this study, we present results from a cohort of multiple advanced cancers treated with restricted anti-PD-(L)1 therapy.

Methods: All patients with advanced cancers treated with anti-PD-(L)1 therapy outside clinical trials at Oulu University Hospital 2014-19 were retrospectively identified from pharmacy records. Clinical variables, treatment history and survival were collected.

Results: 106 patients with median age of 66 years with lung cancer (n = 45, 42.5%), melanoma (n = 30, 28.3%), renal and bladder cancers (GU cancers) (n = 26, 24.5%), head and neck (H&N) cancer (n = 4, 3.8%), and colorectal cancer (n = 1, 0.9%) were included in the study. The median (m) OS for the whole population was 14 months (CI 9.7-18.3), 9 months (CI 6.3-11.7) for patients with no IO-free period (n = 64, 62.1%), and 27.0 months (CI 20.6-33.4, p = 0.000001) for patients (n = 39) with IO-free period. The mIO-free survival was 10.0 months (CI 7.1-12.9) for the whole cohort, 8.0 months (CI 1.7-14.3) for lung cancer, 23.0 months (CI 2.6-43.4) for melanoma, and 14.0 months (CI 0.0-20.4) for GU cancer. From the IO-free cohort, 19 patients needed re-treatment during follow-up, of which 8 were re-challenged with anti-PD-(L)1 therapy. The clinical benefit rate of anti-PD-(L)1 re-challenge was 37.5%.

Conclusions: Our study shows that long IO-free periods can be achieved with limited duration of anti-PD-(L)1 therapy with excellent survival outcomes, and that anti-PD-(L)1 re-challenge is feasible in clinical practice.
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http://dx.doi.org/10.1007/s00432-020-03217-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7324422PMC
August 2020

Osimertinib in T790M-positive and -negative patients with EGFR-mutated advanced non-small cell lung cancer (the TREM-study).

Lung Cancer 2020 05 12;143:27-35. Epub 2020 Mar 12.

Vestre Viken Hospital Trust, Drammen, Norway; Department of Cancer Genetics, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.

Objectives: In non-small cell lung cancer patients with acquired resistance to first- or second-generation EGFR-TKIs, osimertinib is approved in the presence of the T790 M resistance mutation. We assessed the efficacy of osimertinib in both T790M-positive and T790M-negative patients.

Materials And Methods: The TREM-study is an investigator-initiated, multi-centre, single-arm, phase 2 clinical trial conducted in five Northern European countries. Patients with progression on at least one previous EGFR-TKI were assigned to treatment with 80 mg of osimertinib daily until radiological progression or death. Patients were included regardless of the presence of T790 M. The primary endpoint was objective response rate (ORR).

Results: Of 199 included patients, 120 (60 %) were T790M-positive, 52 (26 %) were T790M-negative and 27 (14 %) had unknown T790M-status. 24 % had brain metastases and 15 % had an ECOG performance status of 2. Overall ORR was 48 % (95 % CI, 41 %-55 %), 60 % (51 %-69 %) for T790M-positive patients and 28 % (15 %-41 %) for T790M-negative patients, p < 0.001. ORR for patients with co-occurring del19 vs L858R was 61 % vs 32 %, p = 0.001. Duration of response was similar between the T790M-positive and -negative groups (11.8 vs 10.7 months, p = 0.229). Overall median progression-free survival (PFS) was 8.9 months (95 % CI, 7.4-10.5), and 10.8 vs 5.1 months for T790M-positive vs -negative patients (HR 0.62, p = 0.007). Median overall survival (OS) was 17.9 months (95 % CI, 14.4-21.3). For T790M-positive vs -negative median OS was 22.5 vs 13.4 months, (HR 0.55, p = 0.002).

Conclusions: This study confirms the efficacy of osimertinib for T790M-positive patients. There was also clinically significant activity of osimertinib in a proportion of T790M-negative patients.

Clinical Trial Registration: This trial is registered with ClinicalTrials.gov (NCT02504346).
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http://dx.doi.org/10.1016/j.lungcan.2020.03.009DOI Listing
May 2020

Possibilities of Improving the Clinical Value of Immune Checkpoint Inhibitor Therapies in Cancer Care by Optimizing Patient Selection.

Int J Mol Sci 2020 Jan 15;21(2). Epub 2020 Jan 15.

Department of Oncology and Radiotherapy, Oulu University Hospital and MRC Oulu, 90220 Oulu, Finland.

Immune checkpoint inhibitor (ICI) therapies have become the most important medical therapies in many malignancies, such as melanoma, non-small-cell lung cancer, and urogenital cancers. However, due to generally low response rates of PD-(L)1 monotherapy, both PD-(L)1 combination therapies and novel therapeutics are under large-scale clinical evaluation. Thus far, clinical trials have rather suboptimally defined the patient population most likely to benefit from ICI therapy, and there is an unmet need for negative predictive markers aiming to reduce the number of non-responding patients in clinical practice. Furthermore, there is a strong need for basic tumor immunology research and innovative clinical trials to fully unleash the potential of ICI combinations for the benefit of patients.
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http://dx.doi.org/10.3390/ijms21020556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7014370PMC
January 2020

Elevated CRP levels indicate poor progression-free and overall survival on cancer patients treated with PD-1 inhibitors.

ESMO Open 2019 16;4(4):e000531. Epub 2019 Aug 16.

Department of Oncology and Radiotherapy, MRC Medical Reasearch Center, Oulu University Hospital, Oulu, Finland.

Background: Anti-PD-(L)1 agents are standard of care treatments in various cancers but predictive factors for therapy selection are limited. We hypothesised that markers of systemic inflammation would predict adverse outcomes in multiple cancers treated with anti-PD-(L)1 agents.

Material And Methods: Discovery cohort consisted of patients who were treated with anti-programmed cell death protein-1 (PD-1) agents for advanced melanoma (MEL), non-small cell lung cancer (NSCLC) or renal and bladder cancers (GU) at Oulu University Hospital and had pretreatment C reactive protein (CRP), or neutrophil/lymphocyte values available. As a validation cohort, we collected patients treated with anti-PD-1 agents from three other hospitals in Finland.

Results: In the discovery cohort (n=56, MEL n=23, GU n=17, NSCLC n=16), elevated CRP over the upper limit of normal (ULN) (>10 mg/mL) indicated poor progression-free (PFS; p=0.005) and overall survival (OS; p=0.000004) in the whole population and in MEL subgroup. Elevated neutrophil-to-lymphocyte ratio (>2.65) also indicated inferior PFS (p=0.02) and OS (p=0.009). In the validation cohort (n=107, MEL n=44, NSCLC n=42, GU n=17, other n=4), CRP over ULN also was a strong indicator for poor PFS (p=0.0000008), and OS (p=0.000006) in the whole population, and in MEL and NSCLC also.

Conclusions: Systemic inflammation suggested by elevated CRP is a very strong indicator for adverse prognosis on patients treated with anti-PD-(L)1 agents and has a potential negative predictive value for treatment with anti-PD-(L)1 agents. Prospective trials should investigate whether patients with elevated CRP gain any significant benefit from anti-PD-1 therapy.
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http://dx.doi.org/10.1136/esmoopen-2019-000531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6735669PMC
August 2019

Prognostic and predictive role of tumour-associated macrophages in HER2 positive breast cancer.

Sci Rep 2019 07 29;9(1):10961. Epub 2019 Jul 29.

Department of Oncology and Radiotherapy, Oulu University Hospital, POB 20, 90029, Oulu, Finland.

Disease outcomes of HER2+ breast cancers have dramatically improved after targeted therapies, such as trastuzumab became available. The main mechanism of action of trastuzumab depends on immunoactivation, while immunosuppressive tumour phenotype has been linked to adverse outcomes. Current study included metastatic HER2+ breast cancer patients treated with trastuzumab (n = 40). Immunohistochemistry was conducted to detect nitric oxide synthase 2 (iNOS) expressing M1 polarized and CD163 M2 polarized macrophages, FoxP3 regulatory T-cells (Tregs), CD47 and indoleamine 2,3-dioxygenase 1 (IDO1). High number of iNOS M1-like macrophages, both in the center of the tumour (CT) and invasive margin (IM), was significantly associated with improved survival (p = 0.009) while high expression of IDO1 or CD47 in the malignant cells was associated with worsened prognosis (p = 0.018, p = 0.046). High number of CD163 M2-like macrophages in the CT, but not in the IM, and high number of FoxP3 Tregs in both locations showed non-significant tendencies towards poor prognosis. Moreover, high number of iNOS M1-like macrophages combined with high number of CD8 T-cells in the CT was significantly associated with improved survival (p = 0.0003), and this combined marker predicted patient's ability to remain progression-free without trastuzumab after responding to the therapy (p = 0.003). Current study highlights the role of M1 polarized macrophages alone and in combination with CD8 cells in HER2+ breast cancer.
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http://dx.doi.org/10.1038/s41598-019-47375-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6662906PMC
July 2019

The impact of severe mental illness on lung cancer mortality of patients with lung cancer in Finland in 1990-2013: a register-based cohort study.

Eur J Cancer 2019 09 19;118:105-111. Epub 2019 Jul 19.

Faculty of Social Sciences, University of Tampere, P.O.Box 100, 33014, Finland; Finnish Cancer Registry, Institute for Statistical and Epidemiological Cancer Research, Unioninkatu 22, 00130, Helsinki, Finland.

Background: Although the link between severe mental illness (SMI) and elevated cancer mortality is well established, few studies have examined lung cancer survival and SMI in detail. Our study compared cancer-specific mortality in patients with lung cancer with and without a history of SMI and analysed whether mortality differences could be explained by cancer stage at presentation, comorbidity or differences in cancer treatment.

Methods: We identified patients with their first lung cancer diagnosis in 1990-2013 from the Finnish Cancer Registry, their preceding hospital admissions due to SMI from the Hospital Discharge Register and deaths from the Causes of Death statistics. Competing risk analyses were used to estimate hazard ratios (HRs) for the impact of SMI on mortality.

Results: Of the 37,852 lung cancer cases, 12% had a history of SMI. Cancer-specific mortality differences were found between patient groups in some cancer types after controlling for stage at representation and treatment. Men with a history of psychosis had excess mortality risk (HR = 1.24, 1.06-1.45) in squamous cell carcinoma. Similar excess risk was found among women with psychosis in small-cell carcinoma (HR = 1.76, 1.41-2.19) and in squamous cell carcinoma (HR = 1.67, 1.26-2.20) and among women with mood disorders in adenocarcinoma (HR = 1.37, 1.08-1.74). Patient group differences in HRs in five-year mortality did not markedly change from the 1990s.

Conclusions: We found elevated cancer-specific mortality among persons with a history of SMI. Collaboration between patients, mental healthcare professionals and oncological teams is needed to reduce the mortality gap between patients with cancer with and without SMI.
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http://dx.doi.org/10.1016/j.ejca.2019.06.018DOI Listing
September 2019

An unbiased screen for activating epidermal growth factor receptor mutations.

J Biol Chem 2019 06 5;294(24):9377-9389. Epub 2019 Apr 5.

From the Institute of Biomedicine and Medicity Research Laboratories and

Cancer tissues harbor thousands of mutations, and a given oncogene may be mutated at hundreds of sites, yet only a few of these mutations have been functionally tested. Here, we describe an unbiased platform for the functional characterization of thousands of variants of a single receptor tyrosine kinase (RTK) gene in a single assay. Our een for ctivating utations (iSCREAM) platform enabled rapid analysis of mutations conferring gain-of-function RTK activity promoting clonal growth. The screening strategy included a somatic model of cancer evolution and utilized a library of 7,216 randomly mutated epidermal growth factor receptor () single-nucleotide variants that were tested in murine lymphoid Ba/F3 cells. These cells depend on exogenous interleukin-3 (IL-3) for growth, but this dependence can be compensated by ectopic EGFR overexpression, enabling selection for gain-of-function mutants. Analysis of the enriched mutants revealed EGFR A702V, a novel activating variant that structurally stabilized the EGFR kinase dimer interface and conferred sensitivity to kinase inhibition by afatinib. As proof of concept for our approach, we recapitulated clinical observations and identified the EGFR L858R as the major enriched EGFR variant. Altogether, iSCREAM enabled robust enrichment of 21 variants from a total of 7,216 mutations. These findings indicate the power of this screening platform for unbiased identification of activating RTK variants that are enriched under selection pressure in a model of cancer heterogeneity and evolution.
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http://dx.doi.org/10.1074/jbc.RA118.006336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6579474PMC
June 2019

Association of diagnostic delays to survival in lung cancer: single center experience.

Acta Oncol 2019 Jul 2;58(7):1056-1061. Epub 2019 Apr 2.

a Department of Oncology and Radiotherapy , Oulu University Hospital and MRC Oulu , Oulu , Finland.

Rapid diagnostics and treatment approaches have been applied in many countries to enhance patient satisfaction, but it is unknown whether this leads to improvements in survival. Symptoms initiation, referral, and investigations and their timing, and survival were retrospectively collected from all the patients diagnosed for lung cancer at Oulu University Hospital 2015-2016 ( = 221). Correlation of treatment delays to survival was evaluated in different categories and by tumor stages. Survival analysis showed no statistical difference between patients having below or above median time for the whole clinical pathway (from symptoms to treatment). Subsection analysis of the clinical pathway and division of patients by stage showed improved survival for patients having longer than median times in referral to diagnosis ( = .03) and diagnosis to treatment ( < .0001) for the whole population and in the latter for the stage IV patients as well ( < .0001). In multivariate analysis, long diagnosis to treatment time associated with improved survival while statistical difference was lost in the referral to diagnosis interval. Longer time on diagnostic work-up of lung cancer does not worsen the survival suggesting that fast-track approaches might not improve lung cancer outcomes.
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http://dx.doi.org/10.1080/0284186X.2019.1590635DOI Listing
July 2019

ePROs in the follow-up of cancer patients treated with immune checkpoint inhibitors: a retrospective study.

J Cancer Res Clin Oncol 2019 Mar 21;145(3):765-774. Epub 2019 Jan 21.

Department of Oncology and Radiotherapy, Oulu University Hospital (OYS), MRC Oulu, P.B. 22, 90029, Oulu, Finland.

Purpose: Patient-reported outcome (PRO) follow-up has been shown to improve quality of life (QoL) and survival of cancer patients receiving chemotherapy. Kaiku Health application is a web-based electronic PRO (ePRO) tool which is designed for follow-up of cancer patients receiving immune checkpoint inhibitors (ICI). Purpose of the current study is to investigate whether symptoms collected by Kaiku Health ePRO tool on cancer patients receiving immune checkpoint inhibitors (ICI) follows to symptoms reported in clinical trials and whether coupling of specific symptoms does occur.

Methods: We retrospectively collected data on symptom timing and severity, and QoL of patients followed with Kaiku Health IO module in two Finnish cancer centers between 2017 and 2018. Kaiku Health IO module consists of 18 adaptive questions, which assess the presence and severity of symptoms. Patients were requested (via e-mail) to fill online symptom questionnaires with 3-7 day interval and QoL questionnaires (QLQ-C30) with 1-2 month interval.

Results: The IO module was used to follow 37 patients who had filled in total 559 symptom questionnaires. There was good adherence to ePRO follow-up with a median of 11 questionnaires filled per patient. The reported symptoms and their severity follow closely what has been seen in clinical trials investigating ICIs. Correlation analysis of the symptoms showed the strongest positive correlations between itching and rash; nausea and vomiting, decreased appetite, or stomach pain; cough and shortness of breath.

Conclusions: The results of the current study suggest that real-world symptom data collected through the ePRO application on cancer patients receiving ICI therapy aligns with the data from clinical trials. Correlations between different symptoms occur, which might reflect therapeutic efficiency, side effects, or tumor progression. These correlations should be further investigated with data coupled to clinical outcomes.
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http://dx.doi.org/10.1007/s00432-018-02835-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6394667PMC
March 2019

Early PD-1 Therapy Discontinuation in Responding Metastatic Cancer Patients.

Oncology 2019 31;96(3):125-131. Epub 2018 Oct 31.

Background: Most clinical trials have investigated PD-(L)1 agents until disease progression or severe side effects, but the optimal duration of the treatment remains to be elucidated. Our institutional guideline has restricted maximal PD-(L)1 therapy length to 6 months, and therefore our cohort provides a unique opportunity to investigate the effects of short PD-1 therapy.

Methods: We retrospectively collected all patients who had been treated with PD-1 therapy for metastatic cancer at Oulu University Hospital from 2014 to 2018. Clinical variables, treatment history, and survival were collected.

Results: A total of 59 patients received PD-1 therapy for metastatic disease in lung and genitourinary (renal and bladder) cancers as well as melanoma. Median overall survival was close to what has been seen in clinical trials. Seventeen patients had PD-1 therapy discontinued in response, most of them because of reaching the maximal restricted PD-1 therapy length (n = 12, 70.6%). Patients whose therapy was discontinued in response experienced a long immuno-oncology (IO) therapy-free survival (median 12 months), and only 6 patients had need for therapy re-initiation during the follow-up. We also investigated alternative response evaluation criteria which outperformed conventional RECIST 1.1 in predicting IO therapy-free survival.

Conclusion: The results of the current study suggest that patients whose PD-1 therapy has been discontinued in response can have a long IO therapy-free period without need for a next line of therapy.
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http://dx.doi.org/10.1159/000493193DOI Listing
March 2019

Trastuzumab-induced cardiotoxicity and its risk factors in real-world setting of breast cancer patients.

J Cancer Res Clin Oncol 2018 Aug 5;144(8):1613-1621. Epub 2018 Jun 5.

Department of Medical Oncology and Radiotherapy, Oulu University Hospital, University of Oulu, and MRC Oulu, P.B. 22, 90029, Oulu, Finland.

Purpose: Cardiotoxicity is the most important side effect of trastuzumab treatment. Heart function monitoring is recommended during the treatment which has led to growing use of resources. The aim of this retrospective study was to determine the frequency and timing of trastuzumab cardiotoxicity and its risk factors in real-world setting.

Methods: Single institute, retrospective collection of data on HER2+ breast cancer patients (n = 246) was carried out through a pharmacy search for patients who had received trastuzumab in 2006-2014. Clinical and pathological factors, treatment history, EF measurements, cardiac medications, cardiovascular disease history, cardiac symptoms, and survival data were collected from patient records.

Results: 32 patients (13%) had EF decline ≥ 10%, eleven (4.5%) had EF decline ≥ 20% within 1 year after trastuzumab initiation, and trastuzumab was discontinued due to suspected cardiotoxicity in six patients (2.4%). 49 patients (19.9%) experienced symptoms related to cardiotoxicity during therapy, which accumulated among those with EF drop. Underlying cardiovascular diseases and multiple (≥ 2) cardiac medications were related to EF drop (≥ 20%) and trastuzumab discontinuation. Majority of EF drops (≥ 10%) and trastuzumab discontinuations were seen within 6months of trastuzumab initiation and recovery of EF drop to < 10% of the baseline was seen in most cases (62.5%). There was no statistically significant difference in the survival of patients according to EF drop.

Conclusions: Trastuzumab cardiotoxicity seems to accumulate among patients with underlying cardiac conditions. EF monitoring could be targeted to risk groups without compromising of the cardiac health or survival of HER2-positive breast cancer patients.
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http://dx.doi.org/10.1007/s00432-018-2682-9DOI Listing
August 2018

Prognostic and predictive role of spatially positioned tumour infiltrating lymphocytes in metastatic HER2 positive breast cancer treated with trastuzumab.

Sci Rep 2017 12 21;7(1):18027. Epub 2017 Dec 21.

Department of Oncology and Radiotherapy, Oulu University Hospital, Oulu, 90220, Finland.

Disease outcomes of HER2+ breast cancers have dramatically changed after targeted therapies, such as trastuzumab, came to clinical practice but predictive factors for trastuzumab sensitivity and resistance are frequently unknown. Current work included metastatic breast cancer patients (n = 48), who were treated with trastuzumab and had pre-treatment tumour samples available. The tumours were immunostained for T-cell (CD3, CD8), natural killer (NK)-cell (CD56) and macrophage (CD68) markers and quantitative analysis of the immune cells was carried out using a computer-assisted image analysis in different tumour locations. High number of CD3 and CD8 positive T-cells was associated with significant survival benefit in the center of the tumour (CT) (p = 0.007, p = 0.001) but not in the invasive margin. The number of NK-cells and macrophages in the CT showed non-significant tendency towards improved survival. In subgroup analyses, high density of CD8 CT cells was associated with significant survival benefit in non-bone only disease, in TX or T1-3, and in ER+ tumours (p = 0.006, p = 0.003, p = 0.001). Moreover, high CD8 CT cell density associated significantly with long trastuzumab interruption periods in response. The results suggest important prognostic and predictive role of tumour infiltrating lymphocytes in center of the tumours in metastatic HER2+ breast cancer.
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http://dx.doi.org/10.1038/s41598-017-18266-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5740084PMC
December 2017

Retrospective analysis of HER2 therapy interruption in patients responding to the treatment in metastatic breast cancer.

ESMO Open 2017 16;2(3):e000202. Epub 2017 Jul 16.

Department of Medical Oncology and Radiotherapy, Oulu University Hospital, Oulu, Finland.

Introduction: Human epidermal growth factor receptor 2 (HER2)-targeted-therapy regimens can lead to prolonged tumour responses in metastatic breast cancer. Clinical trials have concerned use of HER2-targeted agents until disease progression, but it is unknown whether the therapy can be interrupted in cases of a good response.

Methods: Single institute, retrospective collection of data on patients with metastatic breast cancer (n=68) was carried out through a pharmacy search for patients who had received trastuzumab in 2006-2014. Clinical and pathological factors, treatment history and survival data were collected from patient records.

Results: Median survival in metastatic disease (all patients) was 32 months and survival times were dramatically different in patients with and without trastuzumab as adjuvant or primary metastatic disease (median 16, 77 and 35 months, respectively; p=0.0004). More importantly, HER2 therapy was intentionally interrupted in 21 responding patients, and these patients experienced long HER2-therapy-free intervals (median 51 months), with excellent long-term survival. A lack of previous adjuvant trastuzumab was the only statistically significant factor predictive of HER2 therapy interruption.

Conclusions: These results from our retrospective study show that HER2 therapy interruption in patients with metastatic breast cancer, who have responded to the therapy, is associated with low risk of rapid disease progression. Study suggests that therapy interruption in cases of response and reinitiation in progression is feasible.
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http://dx.doi.org/10.1136/esmoopen-2017-000202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5519805PMC
July 2017

HER2 regulates cancer stem-like cell phenotype in ALK translocated NSCLC.

Int J Oncol 2017 Aug 21;51(2):599-606. Epub 2017 Jun 21.

Department of Oncology and Radiotherapy, Oulu University Hospital, POB 20, 90029 OYS Oulu, Finland.

We have previously shown that cancer stem-like cells (CSLCs) can mediate therapy resistance in ALK translocated lung cancers. HER2 has been linked to CSLCs in breast cancers and, therefore, we wanted to assess whether HER2 has a role in CSLCs in ALK translocated cancers. ALK translocated cell lines, H3122 and H2228, with variable sensitivity to ALK inhibition were used in the study. HER2 overexpression or knockdown was induced by retro- or lentiviral infections and cells were treated with pharmacological agents targeting HER2 and ALK signaling. Furthermore, tumorigenic properties of the cells were assessed in vitro using colony and sphere formation assays. In the ALK inhibitor sensitive H3122 cells, HER2 overexpression unaltered the primary response to ALK inhibition, but increased CSLC marker expression and enhanced colony and sphere formation and late AKT and ERK1/2 signaling recovery. In the ALK inhibitor semi-sensitive H2228 cells, HER2 knockdown reduced basal expression of CSLC markers, modestly increased sensitivity to ALK inhibition in colony and sphere formation assays, and reduced late AKT and ERK1/2 signaling recovery. In addition, HER2 induced cross activation of other ErbB-members of which HER3 followed most closely the CSLC marker expression and neuregulin-1, a HER3 ligand, or pan-ErbB inhibitor afatinib, were able to alter CSLC marker expression and colony formation. the present study suggests that HER2 has an important role in the regulation of the CSLC phenotype in ALK translocated lung cancers that is mainly orchestrated by HER2/HER3 heterodimers.
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http://dx.doi.org/10.3892/ijo.2017.4048DOI Listing
August 2017

Cancer Stem Cell Properties as Factors Predictive of Chemoresistance in Neoadjuvantly-treated Patients with Ovarian Cancer.

Anticancer Res 2016 Jul;36(7):3425-31

Medical Research Center Oulu, University of Oulu, Oulu, Finland Department of Oncology and Radiotherapy, Oulu University Hospital, Oulu, Finland.

Background/aim: The nuclear factor erytheroid 2-related factor 2-kelch-like ECH-associated protein (NRF2-KEAP1) system and stem cell-like cancer cells are associated with platinum resistance in ovarian cancer. Our objective was to investigate the possible association between platinum resistance, cellular redox-state regulation and stem cell properties in ovarian cancer.

Patients And Methods: Thirty-eight patients with epithelial ovarian cancer were included. All patients had undergone primary diagnostic laparoscopy, platinum-based neoadjuvant chemotherapy, and debulking surgery. Tumor samples were analyzed for NRF2, KEAP1, protein deglycase 1 (DJ1/PARK7), cluster of differentiation molecules 44 (CD44) and 117 (CD117) and aldehyde dehydrogenase 1 (ALDH1) by immunohistochemistry.

Results: Positive pre-treatment expression of CD44 (p=0.013) and stable/increased post-therapy CD44 expression were associated with platinum resistance (p=0.001). Negative pre-treatment expression of cytoplasmic ALDH1 predicted sensitivity to platinum (p=0.017). Pre-treatment nuclear KEAP1 expression was greater in stage II-III cancer (p=0.0003). After neoadjuvant treatment, all samples were nuclear KEAP1-positive (p=0.025) and increased nuclear KEAP1 expression was associated with higher tumor stage (p=0.0001).

Conclusion: CD44 and cytoplasmic ALHD1 could be potential indicators of platinum resistance during neoadjuvant chemotherapy for ovarian cancer.
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July 2016

[Up-to-date drug treatment of disseminated lung cancer--which other drugs are available in addition to conventional cytotoxic agents?].

Duodecim 2016 ;132(6):555-60

In addition to conventional cytotoxic agents, novel drug treatments have in the last few years been introduced for the treatment of non-small cell lung cancer. Whereas some of the novel treatments have brought significant improvement in treatment outcome, the benefit brought about by the treatment has in some cases been quite small in comparison with the costs and adverse effects. In the present review we explore the goals of drug treatments of disseminated lung cancer, assessment of therapeutic benefits as well as most significant research results of novel drug treatments of the lastfew years In addition, we evaluate the effect of the novel drug treatments on Finnish treatment practices.
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June 2016

Nrf2/Keap1 Pathway and Expression of Oxidative Stress Lesions 8-hydroxy-2'-deoxyguanosine and Nitrotyrosine in Melanoma.

Anticancer Res 2016 Apr;36(4):1497-506

Department of Oncology and Radiotherapy, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.

Background/aim: Increased expression and prognostic significance of major redox regulator nuclear factor erythroid-2-related factor (Nrf2) is recognized in many cancers. Our aim was to investigate the role of oxidative stress markers in melanoma.

Materials And Methods: We characterized the immunohistochemical expression of Nrf2, kelch-like ECH-associated protein 1 (Keap1), BRAF(V600E), 8-hydroxy-2'-deoxyguanosine (8-OHdG) and nitrotyrosine in 36 nevi, 14 lentigo maligna and 71 malignant melanomas. We measured Nrf2 expression in melanoma cell lines and conducted cytotoxicity assays combining BRAF/NRAS ablation and H2O2treatment.

Results: Nuclear Nrf2 expression in melanoma correlated with deeper Breslow (p<0.0005), invasive phenotype (Clark III-V) (p=0.011), nodular growth (p=0.001) and worse melanoma-specific survival (p=0.008). Absence of 8-OHdG in the endothelium was a greater significant predictor of poor prognosis (p=0.024) than ulceration (p=0.17) and had a similar impact on prognosis as Breslow (p=0.024). A decrease of Nrf2 followed the BRAF/NRAS inhibition, but combination of inhibitor with H2O2did not increase cytotoxicity.

Conclusion: Nrf2 and 8-OHdG influence prognosis in melanoma.
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April 2016

Bcl-xl and Mcl-1 are the major determinants of the apoptotic response to dual PI3K and MEK blockage.

Int J Oncol 2015 Sep 2;47(3):1103-10. Epub 2015 Jul 2.

Department of Medical Oncology and Radiotherapy and Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, PB22 90029 OYS, Finland.

The dual targeting of PI3K-AKT-mTOR and Ras-Raf-MEK-ERK pathways is a potential anticancer therapy, but unfortunately, the response rate has been low in early phase clinical trials. Pre-clinical models have suggested that an apoptotic response to dual PI3K and MEK targeting is relatively rare and understanding apoptotic avoidance could lead to increased clinical efficiency. This study investigated solid cancer cell lines, which are known to be sensitive to dual PI3K and MEK inhibition but to have a limited apoptotic response. The cells were exposed to dual PI3K and MEK blockage in combination with a panel of additional pharmacological agents and cytotoxicity and apoptosis were analyzed. Our results indicated that the BH3 mimetic ABT-263, the HDAC inhibitor entinostat and the multikinase inhibitor dasatinib increased the cytotoxicity and apoptotic response of dual PI3K and MEK targeting. Furthermore, ABT-263 and entinostat was able to induce apoptosis in combination with single agent PI3K and MEK inhibitors. Protein expression, immunoprecipitation and siRNA knockdown models suggested that Bcl-xl and Mcl-1 were the most important factors circumventing PI3K and/or MEK inhibition-mediated apoptosis. The results suggest that the cytotoxicity of PI3K and/or MEK inhibitor treatments can be augmented by combinatory approaches targeting anti-apoptotic mediators Bcl-xl and Mcl-1.
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http://dx.doi.org/10.3892/ijo.2015.3071DOI Listing
September 2015

EGFR inhibitor and chemotherapy combinations for acquired TKI resistance in EGFR-mutant NSCLC models.

Med Oncol 2015 Jul 17;32(7):205. Epub 2015 Jun 17.

Department of Medical Oncology and Radiotherapy, Oulu University Hospital, PB22, 90029, Oulu, Finland.

Acquired resistance to EGFR TKIs is the most important limiting factor for treatment efficiency in EGFR-mutant NSCLC. Although the continuation of EGFR TKI beyond disease progression in combination with chemotherapy is often suggested as a strategy for treating acquired resistance, the optimal treatment sequence for EGFR TKI and chemotherapy is unknown. In the current work, NSCLC cell lines PC9ER, H1975 and HCC827GR, representing the acquired TKI resistance genotypes (T790M, cMET), were exposed to a chemotherapeutic agent, cisplatin or paclitaxel, in combination with EGFR TKIs (erlotinib, WZ4002) in vitro and analysed for cytotoxicity and apoptotic response. The result showed that all the combinations of EGFR TKIs with a chemotherapeutic agent tested had a synergistic effect on cytotoxicity and increased the apoptotic response. The sequences involving a chemotherapeutic agent concurrently with an EGFR TKI or preceding it were the most efficient strategies. Our in vitro models suggest that the combination of an EGFR TKI and chemotherapy is beneficial in cases of acquired EGFR TKI resistance. Furthermore, the sequence of chemotherapy followed by EGFR TKI is significantly more powerful than the reversed order, so that an intercalated approach is likely to be the most active strategy in clinical use and ought to be tested in a randomized clinical trial.
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http://dx.doi.org/10.1007/s12032-015-0627-6DOI Listing
July 2015

Combining targeted drugs to overcome and prevent resistance of solid cancers with some stem-like cell features.

Oncotarget 2014 Oct;5(19):9295-307

Department of Medical Oncology and Radiotherapy, Oulu University Hospital, University of Oulu, Oulu, Finland.

Treatment resistance significantly inhibits the efficiency of targeted cancer therapies in drug-sensitive genotypes. In the current work, we studied mechanisms for rapidly occurring, adaptive resistance in targeted therapy-sensitive lung, breast, and melanoma cancer cell lines. The results show that in ALK translocated lung cancer lines H3122 and H2228, cells with cancer stem-like cell features characterized by high expression of cancer stem cell markers and/or in vivo tumorigenesis can mediate adaptive resistance to oncogene ablative therapy. When pharmacological ablation of ALK oncogene was accompanied with PI3K inhibitor or salinomycin therapy, cancer stem-like cell features were reversed which was accompanied with decreased colony formation. Furthermore, co-targeting was able to block the formation of acquired resistance in H3122 line. The results suggest that cells with cancer stem-like cell features can mediate adaptive resistance to targeted therapies. Since these cells follow the stochastic model, concurrent therapy with an oncogene ablating agent and a stem-like cell-targeting drug is needed for maximal therapeutic efficiency.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4253435PMC
http://dx.doi.org/10.18632/oncotarget.2424DOI Listing
October 2014

Alternative dosing of dual PI3K and MEK inhibition in cancer therapy.

BMC Cancer 2012 Dec 21;12:612. Epub 2012 Dec 21.

Department of Medical Oncology and Radiotherapy, Oulu University Hospital, Oulu PB22 90029 OYS, Finland.

Background: PI3K/AKT/mTOR and RAS/RAF/MEK/ERK pathways are thought to be the central transducers of oncogenic signals in solid malignancies, and there has been a lot of enthusiasm for developing inhibitors of these pathways for cancer therapy. Some preclinical models have suggested that combining inhibitors of both parallel pathways may be more efficacious, but it remains unknown whether dual inhibition with high enough concentrations of the drugs to achieve meaningful target inhibition is tolerable in a clinical setting. Furthermore, the predictive factors for dual inhibition are unknown.

Methods: Non-small cell lung cancer (NSCLC) cell lines (n=12) with the most frequent oncogenic backgrounds (K-Ras mut n=3, EGFR mut n=3, ALK translocated n=3, and triple-negative n=3) were exposed to PI3K inhibitors (ZSTK474, PI-103) or MEK inhibitor (CI-1040) alone or in combination and analysed with an MTS growth/cytotoxicity assay and statistically by combination index analysis. The activity of the intracellular signaling pathways in response to the inhibitor treatments was analysed with a western blot using phospho-specific antibodies to AKT, ERK1/2, S6, and 4E-BPI. For the differential dosing schedule experiments, additional breast and colon cancer cell lines known to be sensitive to dual inhibition were included.

Results: Two of the 12 NSCLC cell lines tested, H3122 (ALK translocated) and H1437 (triple-negative), showed increased cytotoxicity upon dual MEK and PI3K inhibition. Furthermore, MDA-MB231 (breast) and HCT116 (colon), showed increased cytotoxicity upon dual inhibition, as in previous studies. Activation of parallel pathways in the dual inhibition-sensitive lines was also noted in response to single inhibitor treatment. Otherwise, no significant differences in downstream intracellular pathway activity (S6 and 4E-BPI) were noted between PI3K alone and dual inhibition other than the increased cytotoxicity of the latter. In the alternative dosing schedules two out of the four dual inhibition-sensitive cell lines showed similar cytotoxicity to continuous PI3K and short (15min) MEK inhibition treatment.

Conclusions: Therapy with a dual PI3K and MEK inhibitor combination is more efficient than either inhibitor alone in some NSCLC cell lines. Responses to dual inhibition were not associated with any specific oncogenic genotype and no other predictive factors for dual inhibition were noted. The maximal effect of the dual PI3K and MEK inhibition can be achieved with alternative dosing schedules which are potentially more tolerable clinically.
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http://dx.doi.org/10.1186/1471-2407-12-612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3563486PMC
December 2012

A novel treatment strategy for EGFR mutant NSCLC with T790M-mediated acquired resistance.

Int J Cancer 2012 Aug 8;131(4):970-9. Epub 2011 Nov 8.

Department of Medical Oncology and Radiotherapy, Oulu University Hospital, Oulu, Finland.

The purpose of our study was to identify novel kinase inhibitors for the treatment of genetic subsets of non-small cell lung cancer (NSCLC). NSCLC cell lines (n = 8) with known oncogenic backgrounds (K-Ras, EGFR and EML4-ALK) were exposed to several kinase inhibitors and analyzed for cell growth/cytotoxicity and signaling. Gö6976, a classical protein kinase C inhibitor, showed high potency against mutated EGFR and was further validated in vitro using additional NSCLC lines (n = 4) and Ba/F3 models and in vivo using a xenograft model. Gö6976 was identified to be a potent inhibitor of mutated EGFR with IC50 values from 0.033 nM to 3.3 μM and down regulating phosphorylation of EGFR, AKT and ERK1/2 at concentrations in the range of the IC(50) values. Gö6976 has only a minor effect on wild-type EGFR and cell lines independent of signaling from the mutant EGFR. Most importantly, the activity of Gö6976 remains unchanged despite the presence of the T790M-mediated resistance, and it prevents the occurrence of this resistance in vitro. Gö6976 was also shown to significantly reduce tumor growth in an in vivo xenograft model with a EGFR-mutated NSCLC cell line containing T790M. These findings demonstrate that Gö6976 acts as a potent inhibitor of mutant EGFR despite the presence of T790M, the most important mechanism of acquired resistance for EGFR tyrosine kinase inhibitors, in both in vitro and in vivo models.
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http://dx.doi.org/10.1002/ijc.26461DOI Listing
August 2012
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