Journal articles on the topic 'Chemotherapy biomarker'
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Bukhari, Ali A., and Ranjit K. Goudar. "Thymidylate Synthase as a Predictive Biomarker for Pemetrexed Response in NSCLC." Lung Cancer International 2013 (December 25, 2013): 1–7. http://dx.doi.org/10.1155/2013/436409.
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In recent years, major strides in cancer research have made it possible to select personalized chemotherapy recommendations based on an individual patient’s tumor biology. The prognostic and/or predictive ability of biomarkers seeks to tailor the use of targeted chemotherapy and can result in improved clinical outcomes with reduced toxicity. A proliferation of new technology and pharmacotherapeutics in the setting of current FDA Clinical Laboratory Improvement Amendment (CLIA) standards has resulted in a recent surge in direct-to-physician biomarker tests. However, in the absence of clinical validation, there is the concern that the biomarkers may be utilized prematurely, resulting in improper chemotherapy selection and patient harm. Thymidylate synthase (TS) has been marketed as a predictive biomarker for the use of pemetrexed in NSCLC. We will examine the evidence behind the use of TS as a predictive biomarker to predict response to pemetrexed in NSCLC. At this time, the evidence does not currently support using TS assays to guide chemotherapy selection outside of a clinical research protocol.
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Cho, William CS, Timothy TC Yip, Roger KC Ngan, Tai-Tung Yip, Vladimir N. Podust, Christine Yip, Harry HY Yiu, et al. "ProteinChip Array Profiling for Identification of Disease- and Chemotherapy-Associated Biomarkers of Nasopharyngeal Carcinoma." Clinical Chemistry 53, no. 2 (February 1, 2007): 241–50. http://dx.doi.org/10.1373/clinchem.2005.065805.
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Abstract Background: We previously used ProteinChip array profiling analysis to discover a serum biomarker associated with nasopharyngeal carcinoma (NPC). In this study, we used the same method to examine other biomarkers associated with NPC and response to chemotherapy (CT) in NPC patients. Methods: We performed ProteinChip array analysis in 209 serum samples from 66 relapsed patients before and after salvage CT with gemcitabine and cisplatin or etoposide and cisplatin combinations, 11 patients in remission, and 35 healthy individuals. Intensities of the biomarker peaks were correlated with CT response of the patients and other clinical parameters. Results: We discovered 13 candidate biomarkers associated with different clinical parameters. Two biomarkers (2803 and 3953 Da) were significantly increased in patients compared with controls at all stages of disease. Analysis of pre- and post-CT paired serum samples revealed 7 biomarkers correlated with impact of CT. Of these 7 biomarkers, 2 (2509 and 2756 Da) were significantly increased and 5 (7588, 7659, 7765, 7843, and 8372 Da) were significantly decreased post-CT in either 1 or both CT cohorts. Four biomarkers from pre-CT sera were correlated with CT response, with 3 (2950, 13 510, and 14 855 Da) being significantly decreased and 1 (6701 Da) significantly increased in patients who did not respond to CT. Tandem mass spectrometric sequencing and/or immunoaffinity capture assay identified the 3953 Da biomarker as a fragment of interα-trypsin inhibitor precursor and 7765 Da biomarker as platelet factor-4. Conclusions: Treatment-associated serum biomarkers found might serve to triage NPC patients for appropriate CT treatment.
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Ruddy, Kathryn Jean, Anne M. O'Neill, Kathy Miller, Bryan P. Schneider, Emily Baker, Joseph A. Sparano, Chau T. Dang, Donald W. Northfelt, and George W. Sledge. "Biomarker prediction of chemotherapy-related amenorrhea." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 9508. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.9508.
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9508 Background: Chemotherapy-related amenorrhea (CRA) is associated with infertility and may impact treatment decision-making. We investigated whether anti-mullerian hormone (AMH) levels before chemotherapy predict likelihood of CRA. Methods: 591 patients enrolled on the quality of life substudy of ECOG5103, which randomized breast cancer patients to doxorubicin-cyclophosphamide followed by paclitaxel: 1) alone; 2) with concurrent bevacizumab; or 3) with prolonged bevacizumab. 144 of the 195 women who reported a period <12 months before enrollment consented to serum collection prior to chemotherapy. AMH was measured in 143 with available serum. Participants self-reported menstrual frequency at 12 and 18 months after enrollment. 12-month CRA was defined as no menses for 6 months before the 12-month survey, and 18-month CRA as no menses for 6 months before the 18-month survey. Fisher’s exact test was used to identify associations with CRA. Results: Of the 143, 16 were excluded due to bilateral oophorectomy or initiation of ovarian function suppression within 12 months, and 2 due to missing data at 12 months. In the remaining 125, median age at enrollment was 45 (range 25-55). 103 (82%) had CRA at 12 months, including 68% of patients </= 45 (43/63) and 97% of patients >45 (60/62). Median pre-chemotherapy AMH was 0.11 (range 0.01-8.63). 12-month CRA was more likely in women who received bevacizumab (p<0.01), were >45 (p<0.01), and had AMH </=0.11 (p<0.01) pre-treatment. Hormonal tx was not associated with 12-month CRA (p=0.63). 100 patients were eligible for 18-month CRA analysis: 81 (81%) had CRA, including 63% of patients </= 45 (33/52) and 100% (48/48) of patients >45. 18-month CRA was more likely in women >45 (p<0.01) and with AMH </=0.11 (p<0.01) pre-treatment. Bevacizumab (p=0.15) and hormonal tx (p=0.07) were not statistically significant predictors of 18-month CRA. Conclusions: Pre-chemotherapy AMH predicts risk of CRA at 12 and 18 months, and is a promising biomarker of ovarian reserve in young breast cancer survivors. Longer studies will be needed to ascertain whether lower pre-treatment AMH is associated with increased risk of later infertility. Clinical trial information: NCT00433511.
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Christensen, Ib Jarle, Gunilla Høyer-Hansen, Tine Thurison, Barry Dowell, Julia S. Johansen, Rikke Henriksen, Kristoffer Staal Rohrberg, Nils Brunner, and Hans J. Nielsen. "The prognostic value of seven soluble proteins measured in plasma or serum from patients with colorectal cancer in TNM stages I-III." Journal of Clinical Oncology 30, no. 30_suppl (October 20, 2012): 35. http://dx.doi.org/10.1200/jco.2012.30.30_suppl.35.
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35 Background: In colorectal cancer (CRC) several independent blood-borne biomarkers have been proposed as prognostic and/or predictive markers. However only CEA is at present recommended as a serological CRC biomarker. We have identified 6 other biomarkers and the aim of this study is to see if a combination of markers improves the prognostic and/or predictive value. Methods: Two-hundred and twenty-eight patients with CRC have been included in this study, all with TNM stages I-III. Overall survival (OS) was chosen as the primary endpoint with 93 events and the minimum follow-up was 47 months. Seven biomarkers measured in plasma or serum were analysed: CEA, TIMP-1, the 3 soluble uPAR forms suPAR(I-III), suPAR(I-III)+(II-III) and uPAR(I), PAI-1 and YKL-40. Multivariable analyses of OS were done using regression analysis and results presented by 3 and 5 year OS rates with area under the receiver operating characteristic curve (AUC). All biomarker levels were analysed on the log scale (base 2). Results: High levels of each of the included biomarker were significantly associated in a multivariable analysis (adjusted for age, gender, TNM stage, tumor localization, adjuvant chemotherapy,interaction between adjuvant therapy and biomarker) to poor prognosis in patients not receiving adjuvant chemotherapy. The results are shown for those patients (see Table). The uPAR forms were the only biomarkers significantly associated to OS in patients receiving adjuvant chemotherapy. Combining the markers resulted in an enhanced prediction of 3 and 5 year OS. For TNM stage II patients not receiving adjuvant therapy, the AUC was 0.765 for 3 year OS and 0.745 for 5 year OS. The corresponding AUC’s for TNM stage III were 0.859 and 0.861. Conclusions: The presented combination of blood biomarkers are shown to predict OS with higher precision than any single marker for patients not receiving adjuvant chemotherapy and may provide useful information for use in the management of patients with CRC. [Table: see text]
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Moik, Florian, Sabine Zöchbauer-Müller, Florian Posch, Ingrid Pabinger, and Cihan Ay. "Systemic Inflammation and Activation of Haemostasis Predict Poor Prognosis and Response to Chemotherapy in Patients with Advanced Lung Cancer." Cancers 12, no. 6 (June 18, 2020): 1619. http://dx.doi.org/10.3390/cancers12061619.
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Systemic inflammation and activation of haemostasis are common in patients with lung cancer. Both conditions support tumour growth and metastasis. Therefore, inflammatory and haemostatic biomarkers might be useful for prediction of survival and therapy response. Patients with unresectable/metastatic lung cancer initiating 1st-line chemotherapy (n = 277, 83% non-small cell lung cancer) were followed in a prospective observational cohort study. A comprehensive panel of haemostatic biomarkers (D-dimer, prothrombin fragment 1+2, soluble P-selectin, fibrinogen, coagulation factor VIII, peak thrombin generation), blood count parameters (haemoglobin, leucocytes, thrombocytes) and inflammatory markers (neutrophil-lymphocyte ratio, lymphocyte-monocyte ratio, platelet-lymphocyte ratio, C-reactive protein) were measured at baseline. We assessed the association of biomarkers with mortality, progression-free-survival (PFS) and disease-control-rate (DCR). A biomarker-based prognostic model was derived. Selected inflammatory and haemostatic biomarkers were strong and independent predictors of mortality and therapy response. The strongest predictors (D-dimer, LMR, CRP) were incorporated in a unified biomarker-based prognostic model (1-year overall-survival (OS) by risk-quartiles: 79%, 69%, 51%, 24%; 2-year-OS: 53%, 36%, 23%, 8%; log-rank p < 0.001). The biomarker-based model further predicted shorter PFS and lower DCR. In conclusion, inflammatory and haemostatic biomarkers predict poor prognosis and treatment-response in patients with advanced lung cancer. A biomarker-based prognostic score efficiently predicts mortality and disease progression beyond clinical characteristics.
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Parks, R. M., L. H. Alfarsi, A. R. Green, and K. L. Cheung. "Biology of primary breast cancer in older women beyond routine biomarkers." Breast Cancer 28, no. 5 (June 24, 2021): 991–1001. http://dx.doi.org/10.1007/s12282-021-01266-5.
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Abstract Purpose There are numerous biomarkers which may have potential predictive and prognostic significance in breast cancer. This is extremely important in older adults, who may opt for less aggressive therapy. This work outlines the literature on biological assessment outside of standard biomarkers (defined as ER, PgR, HER2, Ki67) in women ≥ 65 years with primary operable invasive breast cancer, to determine which additional biomarkers are relevant to outcome in older women. Methods Medline and Embase databases were searched. Studies were eligible if included ≥ 50 patients aged ≥ 65 years; stratified results by age; measured a biomarker outside of standard assay and reported patient data. Results A total of 12 studies were appraised involving 5000 patients, measuring 28 biomarkers. The studies were extremely varied in methodology and outcome but three themes emerged: 1. Differences in biomarker expression between younger and older women, indicating that breast cancer in older women is generally less aggressive compared to younger women; 2. Relationship of biomarker expression with survival, suggesting biomarkers which may exclusively predict response to primary treatment in older women; 3. Association of biomarker with chemotherapy, suggesting that older patients should not be declined chemotherapy based on age alone. Conclusion There is evidence to support further investigation of B-cell lymphoma (BCL2), liver kinase (LK)B1, epidermal growth factor receptor (EGFR), cytoplasmic cyclin-E, mucin (MUC)1 and cytokeratins (CKs) as potential predictive or prognostic markers in older women with breast cancer undergoing surgery. Studies exploring these biomarkers in larger cohorts and in women undergoing non-operative therapies are required.
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Adashek, Jacob, Alexey Goloubev, Shumei Kato, and Razelle Kurzrock. "179 Immunotherapy trials lack a biomarker for inclusion: implications for drug development." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A192. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0179.
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BackgroundNext-generation sequencing and other biomarkers have demonstrated the capability to identify potentially pathogenic molecular aberrancies. Immune checkpoint inhibitors (ICI) have benefited patients in almost every oncologic histology. Combining these innovations has transformed how oncologists treat previously untreatable diseases.MethodsThe 413 trials from clinicaltrials.gov website were reviewed using the terms ‘nivolumab’ or ‘pembrolizumab’ between January 1, 2019 and December 31, 2019. Additionally, all 33 interventional therapeutic trials for ‘glioblastoma multiforme’ and 79 for ‘pancreatic cancer’ that were either recruiting, not yet recruiting, or active not recruiting trials between January 1, 2019 and December 31, 2019 were analyzed.ResultsIn total of 413 trials, 57,853 were planned for enrollment with 37 (8.96%) trials requiring a biomarker for entry (n = 5,602 [9.7%]). Overall, there were 41 trials with single-agent immunotherapy planned to enroll 6222 patients and of those trials 7 (17.1%) required a biomarker for enrollment (n = 285 [4.6%]). There were 193 trials with >2 immunotherapies combined planned to enroll 21,360 patients and of those trials 17 (8.8%) required a biomarker for enrollment (n = 1254 [5.9%]). There were 69 trials with immunotherapy and chemotherapy combined planned to enroll 12,354 patients and of those trials 3 (4.3%) required a biomarker for enrollment (n = 83 [0.67%]). There were 58 trials with immunotherapy and targeted therapy combined planned to enroll 11,967 patients and of those trials 6 (10.3%) required a biomarker for enrollment (n = 3244 [27.1%]). There were 52 trials with other immunotherapy combinations (e.g. vaccine) planned to enroll 5950 patients and of those trials 4 (7.7%) required a biomarker for enrollment (736 [12.4%]). Within pancreatic cancer, 31 trials were planned to use immunotherapy (monotherapy, combination, with chemotherapy, with targeted therapy) including 4493 patients total; 5 (16%) of those trials required biomarkers enrolling 309 (7%) patients. Within glioblastoma multiforme, 13 trials were planned to use immunotherapy (monotherapy, combination, with chemotherapy, with targeted therapy) including 730 patients total; 1(8%) of those trials required biomarkers enrolling 10 (1%) patients.ConclusionsFor immunotherapy-based trials in 2019, <10% of patients expected to be enrolled would be selected by a biomarker for inclusion. Precision oncology continues to struggle in the era of ICI with an all-comers approach to patient selection and trial initiation. Selecting patients for trials based on biomarkers may help better identify responders to ICI.
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Chen, Yong-Zi, Youngchul Kim, Hatem H. Soliman, GuoGuang Ying, and Jae K. Lee. "Single drug biomarker prediction for ER− breast cancer outcome from chemotherapy." Endocrine-Related Cancer 25, no. 6 (June 2018): 595–605. http://dx.doi.org/10.1530/erc-17-0495.
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ER-negative breast cancer includes most aggressive subtypes of breast cancer such as triple negative (TN) breast cancer. Excluded from hormonal and targeted therapies effectively used for other subtypes of breast cancer, standard chemotherapy is one of the primary treatment options for these patients. However, as ER− patients have shown highly heterogeneous responses to different chemotherapies, it has been difficult to select most beneficial chemotherapy treatments for them. In this study, we have simultaneously developed single drug biomarker models for four standard chemotherapy agents: paclitaxel (T), 5-fluorouracil (F), doxorubicin (A) and cyclophosphamide (C) to predict responses and survival of ER− breast cancer patients treated with combination chemotherapies. We then flexibly combined these individual drug biomarkers for predicting patient outcomes of two independent cohorts of ER− breast cancer patients who were treated with different drug combinations of neoadjuvant chemotherapy. These individual and combined drug biomarker models significantly predicted chemotherapy response for 197 ER− patients in the Hatzis cohort (AUC = 0.637, P = 0.002) and 69 ER− patients in the Hess cohort (AUC = 0.635, P = 0.056). The prediction was also significant for the TN subgroup of both cohorts (AUC = 0.60, 0.72, P = 0.043, 0.009). In survival analysis, our predicted responder patients showed significantly improved survival with a >17 months longer median PFS than the predicted non-responder patients for both ER− and TN subgroups (log-rank test P-value = 0.018 and 0.044). This flexible prediction capability based on single drug biomarkers may allow us to even select new drug combinations most beneficial to individual patients with ER− breast cancer.
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Demir, Muzaffer, A. Ciftci, Debra Hoppensteadt, G. Altiay, Mahemut Tobu, Omer Iqbal, Dan Fareed, Cafer Adiquzel, Michelle Kujawski, and Jawed Fareed. "ProteinChip Array Profiling and Markers of Inflammation and Thrombin Generation in Plasma Samples from Lung Cancer Patients and Their Modulation by Chemotherapy with or without Warfarin Anticoagulation." Blood 110, no. 11 (November 16, 2007): 3978. http://dx.doi.org/10.1182/blood.v110.11.3978.3978.
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Abstract While the increased prevalence of venous thromboembolic events (VTE) is fully recognized in lung cancer, its pathogenesis is not fully understood. Profiling of surrogate markers of thrombosis and inflammation provides an opportunity to understand the pathogenesis of VTE. More recently, ProteinChip Array technology has provided a novel approach to profile unique biomarkers in cancer patients. Protease activation in these patients results in the generation of unique biomarkers, which can be identified and monitored during the course of patient management. In a prospective, randomized, controlled study patients with inoperable lung cancer (n=100) were randomized to receive A) chemotherapy, radiation and warfarin (INR 1.5–2.5) or B) chemotherapy, radiation without warfarin (n=50). Blood samples were drawn prior to and after the second treatment cycle in both groups A and B. All samples were also analyzed for such inflammation markers as the tumor necrosis factor alpha (TNFa), CD 40 ligand (CD 40L), C-reactive protein (CRP), interleukin 1 beta (IL-1B), asymmetric dimethylarginine (ADMA) and nitric oxide (NO). In addition, prothrombin fragment F1.2 (F1.2), thrombin antithrombin complex (TAT) and functional microparticles were also measured. Proteomic profiling is widely used to identify unique biomarkers in various hemotologic disorders. Albumin was used as control proteins throughout the study. The baseline blood levels of the inflammatory markers and coagulation activation marker were increased in both the warfarin treated and control group. After the second treatment cycle, the warfarin treated group exhibited varying levels of decrease in all of the surrogate markers of coagulation activation and inflammation (13 – 15%). On the other hand, none of the warfarin treated group showed a marked increase in the TNFα, CD40L, NO, F1.2 and TAT (18–30%). No change in the IL-1B was noted in this group. However, CRP levels were markedly reduced (46%). Most of the baseline samples in both groups showed a unique biomarker peak at 11.9 kDa. The prevalence of this unique biomarker peak was decreased after the second cycle of chemotherapy and after the final course of chemotherapy, it was totally diminished. No significant differences in the down regulation of this unique biomarker were obvious in both groups. Since inflammatory markers showed a decrease (13–50%) in the warfarin treated group, whereas the non-warfarin treated group exhibited an increase (18–30%) in all markers except IL-1B, CRP and ADMA, anticoagulation down regulates these mediators. Markers of thrombin generation were also down regulated in the warfarin treated group. The identification of the unique biomarker at 11.9 kDa in both groups and its gradual down regulation eventually leading to diminution in both groups, suggests that chemotherapy and radiation treatment appear to regulate this biomarker. The levels of various inflammatory markers are upregulated in lung cancer suggesting a pathogenic role of this process in lung cancer. Warfarin down regulated the inflammatory process in contrast to the non-warfarin treated group. However, the unique biomarker at 11.9 kDa appears to be regulated by chemotherapy and radiation. The clinical relevance of these observations requires additional investigations.
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Carcò, Daniela, Paolo Castorina, Paola Guardo, Valeria Iachelli, Tecla Pace, Paola Scirè, Rosaria Stanco, et al. "Combination of Interleukin-6, C-Reactive Protein and Procalcitonin Values as Predictive Index of Sepsis in Course of Fever Episode in Adult Haematological Patients: Observational and Statistical Study." Journal of Clinical Medicine 11, no. 22 (November 17, 2022): 6800. http://dx.doi.org/10.3390/jcm11226800.
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Haematological patients represent a vulnerable population to opportunistic infections, mainly due to the disease itself and chemotherapy-induced neutropenia. The level of immune suppression strongly increases the importance of timely antibiotic treatment in order to prevent sepsis-related mortality. During the initial fever episode, serum biomarkers are usually used to estimate the probability of blood stream infection prior to the results of microbial diagnosis. A new serum biomarker combination study on a febrile haematological population, including C-reactive protein (CRP), interleukin-6 (IL−6) and procalcitonin (PCT), is proposed in order to improve their predictive accuracy. In our prospective study, CRP, IL−6 and PCT were evaluated in 34 immunosuppressed haematological patients immediately after the onset of 51 fever episodes, either during the course of standard chemotherapy or high-dose chemotherapy and autologous stem cell transplant. The fever episodes were divided into documented infections and fever alone. Receiver operating characteristic analysis (ROC) was performed for each biomarker and a combination of all three biomarkers (multiROC) to define a new predictive index. Significant differences were evidenced between the two groups (documented infection and no infection) for both PCT and IL−6 (p = 0.03 and p = 0.035, respectively), but none for CRP (p = 0.1). The composite parameter is more reliable than any single biomarker alone, with an area under the curve (AUC) of 79% and with high sensitivity and specificity. IL−6 gave the closest response compared to the composite index. Composite parameters of serum biomarkers could be used for an early diagnosis of infection at fever onset in haematological patients.
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Pennell, Nathan A., Maria E. Arcila, David R. Gandara, and Howard West. "Biomarker Testing for Patients With Advanced Non–Small Cell Lung Cancer: Real-World Issues and Tough Choices." American Society of Clinical Oncology Educational Book, no. 39 (May 2019): 531–42. http://dx.doi.org/10.1200/edbk_237863.
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Over the last decade, the treatment of patients with advanced non–small cell lung cancer (NSCLC) has become reliant on tissue and/or blood biomarkers to help guide treatment decisions. There are now multiple biomarker-defined patient subgroups, with evidence showing that treatment with targeted therapies has superior clinical outcomes when compared with traditional cytotoxic chemotherapy. However, rapid change in the field of precision oncology brings with it the challenge of translating recommendations into clinical practice. In this review, we discuss the major guidelines recommending biomarker testing in NSCLC, as well the logistical challenges to applying these guidelines to patients with NSCLC both in the United States and worldwide. The techniques commonly used for biomarker testing will be discussed, both for tissue- and blood-based biomarkers. Finally, we discuss the challenge of interpreting the results of biomarker testing and using these results to guide treatment decisions.
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Prattes, Juergen, Reinhard B. Raggam, Kim Vanstraelen, Jasmin Rabensteiner, Christoph Hoegenauer, Robert Krause, Florian Prüller, Albert Wölfler, Isabel Spriet, and Martin Hoenigl. "Chemotherapy-Induced Intestinal Mucosal Barrier Damage: a Cause of Falsely Elevated Serum 1,3-Beta-d-Glucan Levels?" Journal of Clinical Microbiology 54, no. 3 (December 30, 2015): 798–801. http://dx.doi.org/10.1128/jcm.02972-15.
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Blood citrulline and intestinal fatty acid binding protein were determined as biomarkers for intestinal mucositis. Biomarker levels were correlated with corresponding serum 1,3-beta-d-glucan levels in 56 samples obtained from 33 cases with underlying hematological malignancies receiving induction chemotherapy. No correlation between biomarkers of intestinal mucositis and BDG levels was observed. (This study has been registered at ClinicalTrials.gov under registration no. NCT01576653.)
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Ademola, AdeyinkaF, ModupeA Kuti, and Adeyemi Ogunleye. "Cardiac biomarker changes with neoadjuvant epirubicin-based chemotherapy." Nigerian Journal of Cardiology 13, no. 2 (2016): 107. http://dx.doi.org/10.4103/0189-7969.187708.
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Aubele, Michaela, Manfred Schmitt, Rudolf Napieralski, Stefan Paepke, Johannes Ettl, Magdalena Absmaier, Viktor Magdolen, et al. "The Predictive Value of PITX2 DNA Methylation for High-Risk Breast Cancer Therapy: Current Guidelines, Medical Needs, and Challenges." Disease Markers 2017 (2017): 1–14. http://dx.doi.org/10.1155/2017/4934608.
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High-risk breast cancer comprises distinct tumor entities such as triple-negative breast cancer (TNBC) which is characterized by lack of estrogen (ER) and progesterone (PR) and the HER2 receptor and breast malignancies which have spread to more than three lymph nodes. For such patients, current (inter)national guidelines recommend anthracycline-based chemotherapy as the standard of care, but not all patients do equally benefit from such a chemotherapy. To further improve therapy decision-making, predictive biomarkers are of high, so far unmet, medical need. In this respect, predictive biomarkers would permit patient selection for a particular kind of chemotherapy and, by this, guide physicians to optimize the treatment plan for each patient individually. Besides DNA mutations, DNA methylation as a patient selection marker has received increasing clinical attention. For instance, significant evidence has accumulated that methylation of the PITX2 (paired-like homeodomain transcription factor 2) gene might serve as a novel predictive and prognostic biomarker, for a variety of cancer diseases. This review highlights the current understanding of treatment modalities of high-risk breast cancer patients with a focus on recommended treatment options, with special attention on the future clinical application of PITX2 as a predictive biomarker to personalize breast cancer management.
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Oloomi, Mana, Neda Moazzezy, and Saeid Bouzari. "Modulation of Molecular Biomarker Expression in Response to Chemotherapy in Invasive Ductal Carcinoma." BioMed Research International 2018 (2018): 1–8. http://dx.doi.org/10.1155/2018/7154708.
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Breast cancer (BC) has varied morphological and biological features and is classified based on molecular and morphological examinations. Molecular classification of BC is based on biological gene-expression profiling. In this study, biomarker modulation was assessed during BC treatment in 30 previously untreated patients. Heterogeneity among patients was pathologically diagnosed and classified into luminal and basal-like immunohistochemical profiles based on estrogen, progesterone, and human epidermal growth factor receptor (ER/PR/HER2) status. Marker heterogeneity was compared with mRNA biomarker expression in patients with BC before and after therapy. Reverse transcription-polymerase chain reaction was performed for molecular characterization. Expression and modulation of biological markers, CK19, hMAM, CEA, MUC, Myc, Ki-67, HER2/neu, ErbB2, and ER, were assessed after treatment, where the expression of the biomarkers CK19, Ki-67, Myc, and CEA was noted to be significantly decreased. Marker expression modulation was determined according to different stages and pathological characteristics of patients; coexpression of three markers (CK19, Ki-67, and Myc) was specifically modulated after therapy. In the histopathologically classified basal-like group, two markers (CK19 and Ki-67) were downregulated and could be considered as diagnostic biomarkers. In conclusion, pathological characteristics and marker variation levels can be evaluated to decide a personalized treatment for patients.
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Wang, Jie, Yanhua Tian, Zhijie Wang, Hua Bai, and Jianchun Duan. "Prognostic prediction of pemetrexed-platinum chemotherapeutic regimen for NSCLC by serum metabolomics." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e20603-e20603. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e20603.
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e20603 Background: Pemetrexed-platinum chemotherapeutic doublet has become a standard schedule as the first-line treatment for advanced non-squamous NSCLC due to its promising efficacy and a favorable toxicity profile. However, chemotherapy resistance inevitably limits the therapeutic effect of this preferred chemotherapeutic regimen, especially for these intrinsically resistant patients. Development of predictive biomarkers to identify those patients who can benefit from this pemetrexed-based regimen has great significance for personalized chemotherapy. Methods: Total 354 patients who were diagnosed with inoperable stage IIIB or IV lung adenocarcinoma (LADC), assigned to receive pemetrexed-platinum doublet chemotherapy as the first-line treatment were enrolled into this prospective study, including 251 cases diagnosed ahead as training set for predictive model establishment and the subsequently diagnosed 103 cases into validation set. Ultraperformance liquid chromatography coupled to mass spectrometry (UPLC-MS) analytical platform were applied to perform the metabolic profiling studies of pre-treatment serum samples. Results: In the training set, eight potential biomarkers, comprising of hypotaurine, taurine, choline, betaine, dimethylglycine, uridine, dodecanoylcarnitine and L-palmitoylcarnitine, were discovered to be differentially expressed between the patients in disease progressive group (PD, n = 53) and disease control group (including CR, PR and SD, n = 198). In the validation set (PD vs non-PD: 23 vs 80), targeted quantitative analysis of these metabolic biomarkers revealed similar levels as that observed in the training set. Logistic regression model was accordingly established based on this eight-metabolic biomarker panel, to discriminate patients who might benefit from this chemotherapy regimen with over 90% accuracy. Conclusions: This prospective study identified blood-based biomarker panel by metabonomics analysis could predict the clinical outcome of pemetrexed-platinum chemotherapy prior to treatment for LADC patients, which needed to be validated by clinical trials of large samples.
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Miura, John Thomas, Thejus T. Jayakrishnan, Daniel Eastwood, Fabian McCartney Johnston, Susan Tsai, Kathleen K. Christians, Kiran Turaga, and T. Clark Gamblin. "Molecular profiling in gastric cancer: Examining potential targets for chemotherapy." Journal of Clinical Oncology 32, no. 3_suppl (January 20, 2014): 131. http://dx.doi.org/10.1200/jco.2014.32.3_suppl.131.
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131 Background: Current NCCN guidelines recommend perioperative epirubicin (E), cisplatin (C), and 5-fluorouracil (F) along with other triple agent derivations as first line therapeutic approaches for operable gastric adenocarcinoma (GC). In this study, we utilized molecular profiling to evaluate expression of chemotherapy targeted biomarkers associated with ECF therapy for GC. Methods: Surgically obtained GC specimens were analyzed by immunohistochemistry for TOP2A, ERCC1, and TS expression (Caris Life Sciences, Phoenix) from 2009-2012. Actionable gene targets were analyzed for mutually exclusive or simultaneous expression. Results: A total of 230 GC specimens were analyzed. The median age of patients was 61 (IQR: 50-72) years with the majority being male (n= 139, 60%). IHC actionable targets included: 60% (n=138) high TOP2A, 55% (n=127) negative ERCC1, and 63% (n=145) negative TS, indicating potential benefit from E, C and F respectively. When analyzing for simultaneous expression profiles of the three genes, only 24 % (n=55) of patients had gene expression levels that suggested sensitivity to all three agents (ECF). Moreover, biomarker results of 6.5% (n=15) of patients demonstrated a potential complete lack of sensitivity to first line ECF therapy. Overall, 61% (n=140) of patients had molecular profiles that indicated sensitivity to two or more agents. Conclusions: Biomarker analysis of GC suggests that there is potential for TOP2A, ERCC1and TS to define patients who have the greatest likelihood of deriving benefit from ECF therapy. 93.5% of patients had the biomarker profile that predicted sensitivity to at least one of these agents. Prospective controlled studies are required to validate the role of TOP2A, TS and ERCC1 in routine management of GC patients.
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Kane, John M., Anthony Magliocco, Qiang Zhang, Dian Wang, Alex Klimowicz, Jonathan Harris, Jeff Simko, Thomas DeLaney, William Kraybill, and David G. Kirsch. "Correlation of High-Risk Soft Tissue Sarcoma Biomarker Expression Patterns with Outcome following Neoadjuvant Chemoradiation." Sarcoma 2018 (2018): 1–10. http://dx.doi.org/10.1155/2018/8310950.
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Background.Sarcoma mortality remains high despite adjuvant chemotherapy. Biomarker predictors of treatment response and outcome could improve treatment selection.Methods. Tissue microarrays (TMAs) were created using pre- and posttreatment tumor from two prospective trials (MGH pilot and RTOG 9514) of neoadjuvant/adjuvant MAID chemotherapy and preoperative radiation. Biomarkers were measured using automated computerized imaging (AQUA or ACIS). Expression was correlated with disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS).Results. Specimens from 60 patients included 23 pretreatment (PRE), 40 posttreatment (POST), and 12 matched pairs (MPs). In the MP set, CAIX, GLUT1, and PARP1 expression significantly decreased following neoadjuvant therapy, but p53 nuclear/cytoplasmic (N/C) ratio increased. In the PRE set, no biomarker expression was associated with DFS, DDFS, or OS. In the POST set, increased p53 N/C ratio was associated with a significantly decreased DFS and DDFS (HR 4.13,p=0.017; HR 4.16,p=0.016), while increased ERCC1 and XPF expression were associated with an improved DFS and DDFS. No POST biomarkers were associated with OS.Conclusions. PRE biomarker expression did not predict survival outcomes. Expression pattern changes after neoadjuvant chemoradiation supports the concepts of tumor reoxygenation, altered HIF-1αsignaling, and a p53 nuclear accumulation DNA damage response.Clinical Trial Registration. NRG Oncology RTOG 9514 is registered with ClinicalTrials.gov. The ClinicalTrials.gov Identifier isNCT00002791.
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Bergsland, Christian H., Jarle Bruun, Marianne G. Guren, Aud Svindland, Merete Bjørnslett, Jørgen Smeby, Merete Hektoen, et al. "Prediction of relapse-free survival according to adjuvant chemotherapy and regulator of chromosome condensation 2 (RCC2) expression in colorectal cancer." ESMO Open 5, no. 6 (November 2020): e001040. http://dx.doi.org/10.1136/esmoopen-2020-001040.
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BackgroundThere is a need for improved selection of patients for adjuvant chemotherapy after resection of non-metastatic colorectal cancer (CRC). Regulator of chromosome condensation 2 (RCC2) is a potential prognostic biomarker. We report on the establishment of a robust protocol for RCC2 expression analysis and prognostic tumour biomarker evaluation in patients who did and did not receive adjuvant chemotherapy.Materials and methodsRCC2 was analysed in 2916 primary CRCs from the QUASAR2 randomised trial and two single-hospital Norwegian series. A new protocol using fluorescent antibody staining and digital image analysis was optimised. Biomarker value for 5-year relapse-free survival was analysed in relation to tumour stage, adjuvant chemotherapy and the molecular markers microsatellite instability, KRAS/BRAFV600E/TP53 mutations and CDX2 expression.ResultsLow RCC2 expression was scored in 41% of 2696 evaluable samples. Among patients with stage I–III CRC who had not received adjuvant chemotherapy, low RCC2 expression was an independent marker of inferior 5-year relapse-free survival in multivariable Cox models including clinicopathological factors and molecular markers (HR 1.45, 95% CI 1.09 to 1.94, p=0.012, N=521). RCC2 was not prognostic in patients who had received adjuvant chemotherapy, neither in QUASAR2 nor the pooled Norwegian series. The interaction between RCC2 and adjuvant chemotherapy for prediction of patient outcome was significant in stage III, and strongest among patients with microsatellite stable tumours (pinteraction=0.028).ConclusionsLow expression of RCC2 is a biomarker for poor prognosis in patients with stage I–III CRC and seems to be a predictive biomarker for effect of adjuvant chemotherapy.
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Tozuka, Takehiro, Rintaro Noro, Masahiro Seike, and Kazufumi Honda. "Benefits from Adjuvant Chemotherapy in Patients with Resected Non-Small Cell Lung Cancer: Possibility of Stratification by Gene Amplification of ACTN4 According to Evaluation of Metastatic Ability." Cancers 14, no. 18 (September 7, 2022): 4363. http://dx.doi.org/10.3390/cancers14184363.
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Surgical treatment is the best curative treatment option for patients with non-small cell lung cancer (NSCLC), but some patients have recurrence beyond the surgical margin even after receiving curative surgery. Therefore, therapies with anti-cancer agents also play an important role perioperatively. In this paper, we review the current status of adjuvant chemotherapy in NSCLC and describe promising perioperative therapies, including molecularly targeted therapies and immune checkpoint inhibitors. Previously reported biomarkers of adjuvant chemotherapy for NSCLC are discussed along with their limitations. Adjuvant chemotherapy after resective surgery was most effective in patients with metastatic lesions located just outside the surgical margin; in addition, these metastatic lesions were the most sensitive to adjuvant chemotherapy. Thus, the first step in predicting patients who have sensitivity to adjuvant therapies is to perform a qualified evaluation of metastatic ability using markers such as actinin-4 (ACTN4). In this review, we discuss the potential use of biomarkers in patient stratification for effective adjuvant chemotherapy and, in particular, the use of ACTN4 as a possible biomarker for NSCLC.
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Patel, Shruti Rajesh, Joerg Herrmann, Robert A. Vierkant, Janet E. Olson, Fergus J. Couch, Antonious Hazim, Jeff A. Sloan, Charles L. Loprinzi, and Kathryn J. Ruddy. "N-Terminal Pro Brain Natriuretic Peptide, sST2, and Galectin-3 Levels in Breast Cancer Survivors." Journal of Clinical Medicine 10, no. 15 (July 27, 2021): 3313. http://dx.doi.org/10.3390/jcm10153313.
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NT-proBNP, soluble ST2 (sST2), and galectin-3 are biomarkers of cardiac dysfunction that have been proposed as identifiers of patients experiencing asymptomatic cardiac dysfunction after anthracycline-based chemotherapy. This study aimed to compare the proportion of breast cancer (BC) survivors with elevated serum levels of these three putative biomarkers by prior receipt of anthracycline (yes vs. no). Five-hundred-eighty survivors of BC who had received anthracycline-based chemotherapy were matched by age and time between diagnosis and serum storage to 580 who had not. Cardiac biomarker levels were analyzed using immunoassays. Analyses were carried out using linear and logistic regression models. Anthracycline recipients had higher values of NT-proBNP than non-recipients (mean 116.0 ng/L vs. 97.0 ng/L, respectively; p < 0.001). Values for ST2 and galectin-3 did not significantly differ by receipt of anthracycline. After further adjustment for age at breast cancer diagnosis, ethnicity, and receipt of trastuzumab, associations between receipt of anthracycline and higher NT-proBNP persisted (p < 0.001), showing that NT-proBNP may be a biomarker of cardiovascular toxicity after receipt of anthracycline-based chemotherapy. Further research to assess the clinical utility of NT-proBNP testing after receipt of anthracycline is recommended. sST2 and galectin-3 do not appear to differentiate between anthracycline recipients and non-recipients amongst breast cancer survivors.
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Yu, Irene S., Francine Aubin, Rachel Goodwin, Jonathan M. Loree, Cheryl Mather, Brandon S. Sheffield, Stephanie Snow, and Sharlene Gill. "Tumor Biomarker Testing for Metastatic Colorectal Cancer: a Canadian Consensus Practice Guideline." Therapeutic Advances in Medical Oncology 14 (January 2022): 175883592211117. http://dx.doi.org/10.1177/17588359221111705.
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The systemic therapy management of metastatic colorectal cancer (mCRC) has evolved from primarily cytotoxic chemotherapies to now include targeted agents given alone or in combination with chemotherapy, and immune checkpoint inhibitors. A better understanding of the pathogenesis and molecular drivers of colorectal cancer not only aided the development of novel targeted therapies but led to the discovery of tumor mutations which act as predictive biomarkers for therapeutic response. Mutational status of the KRAS gene became the first genomic biomarker to be established as part of standard of care molecular testing, where KRAS mutations within exons 2, 3, and 4 predict a lack of response to anti- epidermal growth factor receptor therapies. Since then, several other biomarkers have become relevant to inform mCRC treatment; however, there are no published Canadian guidelines which reflect the current standards for biomarker testing. This guideline was developed by a pan-Canadian advisory group to provide contemporary, evidence-based recommendations on the minimum acceptable standards for biomarker testing in mCRC, and to describe additional biomarkers for consideration.
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Pádua, Diana, Débora Filipa Pinto, Paula Figueira, Carlos Filipe Pereira, Raquel Almeida, and Patrícia Mesquita. "HMGA1 Has Predictive Value in Response to Chemotherapy in Gastric Cancer." Current Oncology 29, no. 1 (December 23, 2021): 56–67. http://dx.doi.org/10.3390/curroncol29010005.
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Gastric cancer is a serious health problem worldwide. Although its incidence is decreasing, the five-year survival rate remains low. Thus, it is essential to identify new biomarkers that could promote better diagnosis and treatment of patients with gastric cancer. High-mobility group AT-hook 1 (HMGA1) is a non-histone, chromatin-binding protein that has been found overexpressed in several tumor types. It has been correlated with invasion, metastasis, and drug resistance, leading to worse patient survival. The aim of this work was to evaluate the clinical value of HMGA1 in gastric cancer. HMGA1 expression was analyzed by immunohistochemistry in a single hospital series (n = 323) of gastric adenocarcinoma cases (stages I to IV) with clinicopathological and treatment data. In this series, HMGA1 expression showed no significant relevance as a prognostic biomarker. Nevertheless, a significantly better overall survival was observed in cases with high levels of HMGA1 when they were treated with chemotherapy, compared to the nontreated ones, implying that they can benefit more from treatment than patients with low expression of HMGA1. We thereby show for the first time that HMGA1 expression has a substantial value as a biomarker of response to chemotherapy in gastric cancer.
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Wang, Zixuan, Kaiyuan Xing, Bo Zhang, Yanru Zhang, Tengyue Chai, Jingkai Geng, Xuexue Qin, Xinxin Zhang, and Chaohan Xu. "Identification of Prognostic Gene Signatures by Developing a scRNA-Seq-Based Integration Approach to Predict Recurrence and Chemotherapy Benefit in Stage II–III Colorectal Cancer." International Journal of Molecular Sciences 23, no. 20 (October 18, 2022): 12460. http://dx.doi.org/10.3390/ijms232012460.
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Prospective identification of robust biomarkers related to prognosis and adjuvant chemotherapy has become a necessary and critical step to predict the benefits of adjuvant therapy for patients with stage II–III colorectal cancer (CRC) before clinical treatment. We proposed a single-cell-based prognostic biomarker recognition approach to identify and construct CRC up- and down-regulated prognostic signatures (CUPsig and CDPsig) by integrating scRNA-seq and bulk datasets. We found that most genes in CUPsig and CDPsig were known disease genes, and they had good prognostic abilities in CRC validation datasets. Multivariate analysis confirmed that they were two independent prognostic factors of disease-free survival (DFS). Significantly, CUPsig and CDPsig could effectively predict adjuvant chemotherapy benefits in drug-treated validation datasets. Additionally, they also performed well in patients with CMS4 subtype. Subsequent analysis of drug sensitivity showed that expressions of these two signatures were significantly associated with the sensitivities of CRC cell lines to multiple drugs. In summary, we proposed a novel prognostic biomarker identification approach, which could be used to identify novel prognostic markers for stage II–III CRC patients who will undergo adjuvant chemotherapy and facilitate their further personalized treatments.
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Kaplan, Richard, Timothy Maughan, Angela Crook, David Fisher, Richard Wilson, Louise Brown, and Mahesh Parmar. "Evaluating Many Treatments and Biomarkers in Oncology: A New Design." Journal of Clinical Oncology 31, no. 36 (December 20, 2013): 4562–68. http://dx.doi.org/10.1200/jco.2013.50.7905.
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There is a pressing need for more-efficient trial designs for biomarker-stratified clinical trials. We suggest a new approach to trial design that links novel treatment evaluation with the concurrent evaluation of a biomarker within a confirmatory phase II/III trial setting. We describe a new protocol using this approach in advanced colorectal cancer called FOCUS4. The protocol will ultimately answer three research questions for a number of treatments and biomarkers: (1) After a period of first-line chemotherapy, do targeted novel therapies provide signals of activity in different biomarker-defined populations? (2) If so, do these definitively improve outcomes? (3) Is evidence of activity restricted to the biomarker-defined groups? The protocol randomizes novel agents against placebo concurrently across a number of different biomarker-defined population-enriched cohorts: BRAF mutation; activated AKT pathway: PI3K mutation/absolute PTEN loss tumors; KRAS and NRAS mutations; and wild type at all the mentioned genes. Within each biomarker-defined population, the trial uses a multistaged approach with flexibility to adapt in response to planned interim analyses for lack of activity. FOCUS4 is the first test of a protocol that assigns all patients with metastatic colorectal cancer to one of a number of parallel population-enriched, biomarker-stratified randomized trials. Using this approach allows questions regarding efficacy and safety of multiple novel therapies to be answered in a relatively quick and efficient manner, while also allowing for the assessment of biomarkers to help target treatment.
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Walsh, Christine S., Seishi Ogawa, Hisae Karahashi, Daniel R. Scoles, James C. Pavelka, Hang Tran, Carl W. Miller, et al. "ERCC5 Is a Novel Biomarker of Ovarian Cancer Prognosis." Journal of Clinical Oncology 26, no. 18 (June 20, 2008): 2952–58. http://dx.doi.org/10.1200/jco.2007.13.5806.
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Purpose To identify a biomarker of ovarian cancer response to chemotherapy. Patients and Methods Study participants had epithelial ovarian cancer treated with surgery followed by platinum-based chemotherapy. DNA and RNA were isolated from frozen tumors and normal DNA was isolated from matched peripheral blood. A whole-genome loss of heterozygosity (LOH) analysis was performed using a high-density oligonucleotide array. Candidate genomic areas that predicted enhanced response to chemotherapy were identified with Cox proportional hazards methods. Gene expression analyses were performed through microarray experiments. Candidate genes were tested for independent effects on survival using Cox proportional hazards models, Kaplan-Meier survival curves, and the log-rank test. Results Using a whole-genome approach to study the molecular determinants of ovarian cancer response to platinum-based chemotherapy, we identified LOH of a 13q region to predict prolonged progression-free survival (PFS; hazard ratio, 0.23; P = .006). ERCC5 was identified as a candidate gene in this region because of its known function in the nucleotide excision repair pathway, the unique DNA repair pathway that removes platinum-DNA adducts. We found LOH of the ERCC5 gene locus and downregulation of ERCC5 gene expression to predict prolonged PFS. Integration of genomic and gene expression data shows a correlation between 13q LOH and ERCC5 gene downregulation. Conclusion ERCC5 is a novel biomarker of ovarian cancer prognosis and a potential therapeutic target of ovarian cancer response to platinum chemotherapy.
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Kopetz, Scott. "“Right Drug for the Right Patient”: Hurdles and the Path Forward in Colorectal Cancer." American Society of Clinical Oncology Educational Book, no. 33 (May 2013): e115-e120. http://dx.doi.org/10.14694/edbook_am.2013.33.e115.
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Predictive biomarkers have been heralded as the way to develop the “right drug for the right patient.” However, despite many studies incorporating novel biomarkers with targeted therapies, there has been little progress over the 5 years since the identification of KRAS mutations' ability to predict resistance to epidermal growth factor receptor (EGFR) monoclonal antibodies. Recently approved therapeutics (regorafenib, aflibercept) or label extensions for existing therapies (bevacizumab) lack companion biomarkers. The current model of biomarker development, “target-based biomarker” design, attempts to identify individual biomarkers that are closely tied to the activity of a particular treatment. There are several limitations to prospective utilization of predictive biomarkers in novel therapy development, including technical validation of the assay and the logistics of timely biomarker determination with available material that limit the options. Tumor heterogeneity, both between different regions in the tumor and as a result of changes induced over time and under the selective pressure of chemotherapy, can reduce the precision of biomarker determination. Biomarkers present in low frequencies are increasingly common in drug development and will require efficient screening infrastructure to be feasible. Although development efforts will continue in the current target-based biomarker model for the near future, it is increasingly apparent that a new model is needed. A “taxonomy-based biomarker” model has been proposed, which is less tied to novel drug development and instead attempts to classify individual tumors based on their intrinsic biology. This requires integrating multiple characteristics of the tumors, including gene mutations, amplifications, methylation, as well as RNA and protein expression. Identification of the taxonomy of colorectal cancer will then allow more efficient development of targeted agents that can leverage the distinct molecular vulnerabilities of the resulting subsets. A transition to a taxonomy-based biomarker model would provide the classification structure and biologic insights needed to advance the ultimate goal of the right drug for the right patient.
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Nikas, Jason B., Walter C. Low, and Paul A. Burgio. "Prognosis of Treatment Response (Pathological Complete Response) in Breast Cancer." Biomarker Insights 7 (January 2012): BMI.S9387. http://dx.doi.org/10.4137/bmi.s9387.
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Pertaining to the female population in the USA, breast cancer is the leading cancer in terms of annual incidence rate and, in terms of mortality, the second most lethal cancer. There are currently no biomarkers available that can predict which breast cancer patients will respond to chemotherapy with both sensitivity and specificity > 80%, as mandated by the latest FDA requirements. In this study, we have developed a prognostic biomarker model (complex mathematical function) that–-based on global gene expression analysis of tumor tissue collected during biopsy and prior to the commencement of chemotherapy–-can identify with a high accuracy those patients with breast cancer (clinical stages I–III) who will respond to the paclitaxel-fluorouracil-doxorubicin-cyclophosphamide chemotherapy and will experience pathological complete response (Responders), as well as those breast cancer patients (clinical stages I–III) who will not do so (Non-Responders). Most importantly, both the application and the accuracy of our breast cancer prognostic biomarker model are independent of the status of the hormone receptors ER, PR, and HER2, as well as of the ethnicity and age of the subjects. We developed our prognostic biomarker model with 50 subjects [10 responders (R) and 40 non-responders (NR)], and we validated it with 43 unknown (new and different) subjects [10 responders (R) and 33 non-responders (NR)]. All 93 subjects were recruited at five different clinical centers around the world. The overall sensitivity and specificity of our prognostic biomarker model were 90.0% and 91.8%, respectively. The nine most significant genes identified, which comprise the input variables to the mathematical function, are involved in regulation of transcription; cell proliferation, invasion, and migration; oncogenesis; suppression of immune response; and drug resistance and cancer recurrence.
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Evran, Ebru, Hilal Şahin, Kübra Akbaş, Sadik Çiğdem, and Esra Gündüz. "Investigation of MACC1 Gene Expression in Head and Neck Cancer and Cancer Stem Cells." Clinical & Investigative Medicine 39, no. 6 (December 1, 2016): 77. http://dx.doi.org/10.25011/cim.v39i6.27506.
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Purpose: By investigating the MACC1 gene (metastasis-associated in colon cancer 1) in cancer stem cells (CSC) resistant to chemotherapy and in cancer stem cells (CSC) resistant to chemotherapy and in cancer cells (CS) sensitive to chemotherapy we determineda steady expression in both types of cells in head and neck cancer. In conformity with the result we examined if this gene could be a competitor gene for chemotherapy. According to literature, the MACC1 gene shows a clear expression in head and neck cancer cells [1]. Here we examined MACC1 expression in CSC and investigated it as a possible biomarker.
Methods: Our experiments were performed in the UT -SCC -74 in primary head and neck cancer cell line. We examined the MACC -1 gene expression by Real Time PCR from both isolated CSC and CS.
Results: Expression of MACC -1 gene of cancer stem cells showed an two-fold increase compared with cancer cells. Based on the positive expression of MACC1 in both CS and CSC, this gene may serve as a potential biomarker in head and neck cancer. By comparing the results of this study with the novel features of MACC1, two important hypotheses could be examined. The first hypothesis is that MACC1 is a possible transcripton factor in colon cancer, which influences a high expression of CSC in head and neck and affects the expression of three biomarkers of the CSC control group biomarkers. The second hypothesisis is that the positive expression of MACC1 in patients with a malignant prognosis of tongue cancer, which belongs to head and neck cancer types, operates a faster development of CSC to cancer cells.
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Zhu, Feng, Jing Ma, Dongdong Ru, Ningning Wu, Yunhua Zhang, Huiyuan Li, Xiaoli Liu, et al. "Plasma DNA Integrity as a Prognostic Biomarker for Colorectal Cancer Chemotherapy." Journal of Oncology 2021 (May 26, 2021): 1–10. http://dx.doi.org/10.1155/2021/5569783.
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Objectives. To verify whether the concentrations and integrity index of circulating cell-free DNA (cfDNA) in serum may be clinically useful for the progression monitoring of colorectal cancer (CRC) patients. Methods. Serum samples were collected from 76 primary CRC patients who underwent surgery, including 60 with chemotherapy and 43 with follow-up. Long (247 bp) and short (115 bp) DNA fragments in serum were detected by real-time quantitative PCR by amplifying the ALU repeats. Ten serum traditional biomarkers levels were detected by chemiluminescence immunoassay assay. Results. The median DNA integrity index (ALU247/ALU115) of serum DNA in the preoperative group was significantly higher than those in the postchemotherapy and the follow-up groups, while cfDNA concentration (ALU115) was significantly lower in the preoperative group compared with the postchemotherapy and the follow-up groups. CEA and CA242 were significantly lower in the postoperative group than in the preoperative group. Conclusions. Serum DNA integrity index (ALU247/115) may prove to be a promising candidate biomarker for prognostic prediction of CRC who underwent chemotherapy and during short-term follow-up.
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Haykal, Maria M., Sylvie Rodrigues-Ferreira, and Clara Nahmias. "Microtubule-Associated Protein ATIP3, an Emerging Target for Personalized Medicine in Breast Cancer." Cells 10, no. 5 (May 1, 2021): 1080. http://dx.doi.org/10.3390/cells10051080.
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Breast cancer is the leading cause of death by malignancy among women worldwide. Clinical data and molecular characteristics of breast tumors are essential to guide clinician’s therapeutic decisions. In the new era of precision medicine, that aims at personalizing the treatment for each patient, there is urgent need to identify robust companion biomarkers for new targeted therapies. This review focuses on ATIP3, a potent anti-cancer protein encoded by candidate tumor suppressor gene MTUS1, whose expression levels are markedly down-regulated in breast cancer. ATIP3 is a microtubule-associated protein identified both as a prognostic biomarker of patient survival and a predictive biomarker of breast tumors response to taxane-based chemotherapy. We present here recent studies pointing out ATIP3 as an emerging anti-cancer protein and a potential companion biomarker to be combined with future personalized therapy against ATIP3-deficient breast cancer.
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Yarden, Ronit, and Tamara Springer. "Precision medicine in colorectal cancer: Gaps in patients’ literacy of biomarkers and genetic testing." Journal of Clinical Oncology 38, no. 4_suppl (February 1, 2020): 55. http://dx.doi.org/10.1200/jco.2020.38.4_suppl.55.
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55 Background: Colorectal cancer (CRC) is the second leading cause of cancer death in the united states. Despite some advances, mortality is high and the 5-year overall survival from metastatic disease (mCRC) is only 14%. CRC is a heterogeneous disease with multiple subtypes defined by location, microsatellite integrity, specific genetic alterations and potentially age. The identification of specific driving mutation/s led to the development of targeted therapies. Patients are eligible for these treatments based on their personalized tumor biomarker profile. ASCO guidelines recommend that all patients with mCRC are tested for KRAS mutations. This mutation is present in ~40% of CRC patients, and serves as a biomarker for lack of response to EGFR therapy. Similarly, high microsatellite instability (MSI-H) suggests an inferior response to commonly used chemotherapy and favorable response to immunotherapy. Methods: We conducted an online survey to assess patients, survivors and caregivers’ knowledge and understanding of biomarker testing. Results: Among the 210 participants in this cross-sectional study, 81% of participants reported ‘no familiarity’ with the term biomarkers at the time of diagnosis, while 73% reported awareness at the time of the survey. Yet, when presented with specific biomarkers, majority of participants were not familiar with any of those biomarkers. Of the 103 stage IV respondents, only 14% were familiar with the four common CRC biomarkers, and only 1 in 4 reported their tumor was tested prior to treatment initiation. Nearly half of the respondents cited their physician and medical team as the main source of biomarker information (46%) while the other half reported their medical team never informed them of biomarkers. Overall, 50% of participants indicated that advocacy groups, medical websites, and various online resources were their main sources of biomarker information. Disparities of biomarker awareness were noted based on gender, age, and area of residency. Conclusions: Taken together, patients do not fully comprehend the meaning and implications of biomarker testing. Medical teams should make a greater effort to inform their patients early on in their treatment.
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Chaft, Jamie E., Yu Shyr, Boris Sepesi, and Patrick M. Forde. "Preoperative and Postoperative Systemic Therapy for Operable Non–Small-Cell Lung Cancer." Journal of Clinical Oncology 40, no. 6 (February 20, 2022): 546–55. http://dx.doi.org/10.1200/jco.21.01589.
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Cisplatin-based adjuvant chemotherapy remains the standard of care for patients with resected stage II or III non–small-cell lung cancer. However, biomarker-informed clinical trials are starting to push the management of early-stage lung cancer beyond cytotoxic chemotherapy. This review explores recent and ongoing studies focused on improving cytotoxic chemotherapy and incorporating targeted and immunotherapies in the management of early-stage, resectable lung cancer. Adjuvant osimertinib for patients with EGFR-mutant tumors, preoperative chemoimmunotherapy, and adjuvant immunotherapy could improve outcomes for selected patients with resectable lung cancer, and ongoing or planned studies leveraging biomarkers, immunotherapy, and targeted therapy may further improve survival. We also discuss the unique barriers associated with clinical trials of early-stage lung cancer and the need for innovative trial designs to overcome these challenges.
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Ma, Zhiyao, Marissa Williams, Yuen Yee Cheng, and Wai K. Leung. "Roles of Methylated DNA Biomarkers in Patients with Colorectal Cancer." Disease Markers 2019 (March 3, 2019): 1–8. http://dx.doi.org/10.1155/2019/2673543.
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Colorectal cancer (CRC) is a leading cancer globally; therefore, early diagnosis and surveillance of this cancer are of paramount importance. Current methods of CRC diagnosis rely heavily on endoscopy or radiological imaging. Noninvasive tests including serum detection of the carcinoembryonic antigen (CEA) and faecal occult blood testing (FOBT) are associated with low sensitivity and specificity, especially at early stages. DNA methylation biomarkers have recently been found to have higher accuracy in CRC detection and enhanced prediction of prognosis and chemotherapy response. The most widely studied biomarker in CRC is methylated septin 9 (SEPT9), which is the only FDA-approved methylation-based biomarker for CRC. Apart from SEPT9, other methylated biomarkers including tachykinin-1 (TAC1), somatostatin (SST), and runt-related transcription factor 3 (RUNX3) have been shown to effectively detect CRC in a multitude of sample types. This review will discuss the performances of various methylated biomarkers used for CRC diagnosis and monitoring, when used alone or in combination.
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Potenza, Enrico, Giulia Parpinel, Maria E. Laudani, Chiara Macchi, Luca Fuso, and Paolo Zola. "Prognostic and predictive value of combined HE-4 and CA-125 biomarkers during chemotherapy in patients with epithelial ovarian cancer." International Journal of Biological Markers 35, no. 4 (October 30, 2020): 20–27. http://dx.doi.org/10.1177/1724600820955195.
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Introduction: At present there is no predictive value univocally associated with the success of chemotherapy. Biomarkers produced by ovarian cancer (HE4 and Ca125) could have a good prognostic significance. The aim of this study is to prove the ability of biomarkers to identify patients with the highest risk of non-optimal response during the chemotherapy, and to predict which patients will most likely develop recurrence of disease. Methods: We analyzed 78 patients with epithelial ovarian cancers who underwent surgery in the biennium 2016–2017. All the patients underwent chemotherapy after surgery or interval debulking surgery following neoadjuvant therapy. Serum levels of HE4 and Ca125 were measured at diagnosis and at each cycle of chemotherapy. We established the degree of response to the treatment by computed tomography scan, and the patients were followed up (median: 10 months). The parameters of progression-free survival and disease-free survival were related to serum levels of biomarkers. Results: Both CA125 and HE4 values became negative at the fourth cycle in the patients with good response to chemotherapy. HE4 increased earlier than Ca125. The parameters that best correlated with a long progression-free survival were: negativization of the marker after the third cycle of chemotherapy (HE4: odds ratio (OR) 5.5; Ca125: OR 9.1) and biomarker serum levels lower than the mean value in the affected population at the time of diagnosis (HE4: OR 3.4; Ca125: OR 3.7). Conclusions: We can conclude that the monitoring of HE4 and Ca125 during chemotherapy, especially at the third cycle, is recommended, because their variation is a good prognostic factor.
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Nishioka, Yujiro, Junichi Shindoh, Yoshinori Inagaki, Wataru Gonoi, Jun Mitsui, Hiroyuki Abe, Ryuji Yoshioka, et al. "Host MICA Polymorphism as a Potential Predictive Marker in Response to Chemotherapy for Colorectal Liver Metastases." Digestive Diseases 36, no. 6 (2018): 437–45. http://dx.doi.org/10.1159/000490411.
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Background: Understanding the genetic background of a tumor is important to better stratify patient prognosis and select optimal treatment. For colorectal liver metastases (CLM), however, clinically available biomarkers remain limited. Methods: After a comprehensive sequencing of 578 cancer-related genes in 10 patients exhibiting very good/poor responses to chemotherapy, the A5.1 variant of the MICA gene was selected as a potential biomarker for CLM. The clinical relevance of MICA A5.1 was then investigated in 58 patients who underwent CLM resection after chemotherapy. Results: The A5.1 variant was observed in 16 (27.6%) patients examined using direct DNA sequencing, and a very high concordance rate (56/58, 96.6%) for the MICA variant was confirmed between tumor tissues and normal liver parenchyma. A multivariate analysis of 38 patients with no history of treatment with anti-EGFR antibodies confirmed that MICA A5.1 was significantly correlated with an optimal CT morphologic response (OR 11.67; 95% CI 2.08–65.60; p = 0.005) and tended to be correlated with a tumor viability of < 20% after chemotherapy (OR 5.91; 95% CI 0.97–36.02; p = 0.054). MICA A5.1 was also associated with a decreased risk of progression after CLM resection. Conclusion: The MICA A5.1 polymorphism was associated with a better CT morphologic response to chemotherapy and a reduced risk of relapse after CLM resection. Given the high concordance rate in MICA variants between normal liver tissue and CLM, the genetic background of the host could be a new biomarker for CLM.
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Boys, Rachel. "P06 Improving renal function monitoring during chemotherapy- a role for cystatin C?" Archives of Disease in Childhood 105, no. 9 (August 19, 2020): e8.2-e9. http://dx.doi.org/10.1136/archdischild-2020-nppg.15.
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AimRenal toxicity causes major morbidity following chemotherapy- abnormal iGFRs may be detected in up to 73.7% of patients.1 Creatinine is universally used as a biomarker to track fluctuating function and to calculate surrogate glomerular filtration rate (GFR) in the form of estimating equations.2 There is concern regarding the suitability of creatinine as a biomarker in this population, and it is proposed that cystatin C as a biomarker alone and also included in estimating equations may offer improved clinical suitability and accuracy.3MethodsIn this prospective, longitudinal study over a period of 18 months, 132 combined isotope GFR (iGFR), creatinine and cystatin C measurements were taken from 48 paediatric oncology patients at a Northern Children’s Hospital. Correlation and agreement analysis was performed for both individual biomarkers and estimating equations. Sensitivity data, along with ROC curve analysis was performed for all biomarkers and estimating equations. Data from three identified patients was isolated to examine individual patient variation over time.ResultsCreatinine identified only 1/32 patients with an abnormal iGFR (<90 ml/min/1.73 m2) compared to cystatin C which identified 12/32. Creatinine values and both estimating equations failed to change significantly over a period of declining iGFR though cystatin C did show a significant inverse increase (p<0.05). Bland Altman analysis for both the creatinine and combined equation showed poor agreement (mean difference -64 ml/min/1.3 m2 and -20 ml/min/1.73 m2 respectively). All biomarkers and equations showed poor sensitivity to detect an abnormal iGFR either below 70 ml/min/1.73 m2 or 90 ml/min/1.73 m2. A transformation factor applied to the equations significantly improved the sensitivity and clinical applicability of all equations. The data from three individual patients failed to reveal any significant intra-patient relationships.ConclusionData from this study cannot support the use of creatinine or cystatin C as a single biomarker to monitor renal function in children undergoing chemotherapy. Newer cystatin C and creatinine combined equations, whilst offering statistical superiority, do not offer the clinical superiority to replace iGFR or provide a tool for accurate dose calculations. A transformation factor can be applied to the results gained from the estimating equations to significantly improve the detection of abnormal iGFR, though work in other patient cohorts is needed to support this. Previous work also supported the use of a transformation factor, though application of their transformation factor to this current cohort failed to replicate the 100% sensitivity findings previously demonstrated4. Three patients were identified from the cohort and their paired iGFR and estimated GFR were monitored prospectively, over a period of approximately a year. Significant variation was observed between iGFR and eGFR at each time point for all three patients and therefore personalisation of GFR estimation from baseline iGFR and demographic data could not be proposed. This requires exploration in a larger cohort with the possible inclusion of additional baseline variables.ReferencesCRUK Survival trends over time in Children’s Cancers. 1.2015. https://www.cancerresearchuk.org/health-professional/cancer-statistics/childrens-cancers/survival#heading-Two Accessed 28th March 2019.NICE ( 2013) CG169 Acute kidney injury: Prevention, detection and management of acute kidney injury up to the point of renal replacement therapy.Barnfield, MC, Burniston, MT, Reid, U, et al. Cystatin C in assessment of glomerular filtration rate in children and young adults suffering from cancer. Nuclear Medicine Communications 2013;34:609–614.Dodgshun, AJ, Quinlan, C, Sullivan, MJ. Cystatin C based equation accurately estimates glomerular filtration rate in children with solid and central nervous system tumours: enough evidence to change practice? Pediatric Blood and Cancer 2016;63:1535–1538.
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Weber, Wolfgang A. "Positron Emission Tomography As an Imaging Biomarker." Journal of Clinical Oncology 24, no. 20 (July 10, 2006): 3282–92. http://dx.doi.org/10.1200/jco.2006.06.6068.
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Positron emission tomography (PET) allows noninvasive, quantitative studies of various biologic processes in the tumor tissue. By using PET, investigators can study the pharmacokinetics of anticancer drugs, identify various therapeutic targets and monitor the inhibition of these targets during therapy. Furthermore, PET provides various markers to assess tumor response early in the course of therapy. A significant number of studies have now shown that changes in tumor glucose utilization during the first weeks of chemotherapy are significantly correlated with patient outcome. These data suggest that PET may be used as a sensitive test to assess the activity of new cytotoxic agents in phase II studies. Furthermore, early identification of nonresponding tumors provides the opportunity to adjust treatment regimens according to the individual chemosensitivity of the tumor tissue. However, further prospective and randomized validation of PET is still required before PET controlled chemotherapy can be used in clinical practice.
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Shenasa, Elahe, Elisabeth Specht Stovgaard, Maj-Britt Jensen, Karama Asleh, Nazia Riaz, Dongxia Gao, Samuel Leung, Bent Ejlertsen, Anne-Vibeke Laenkholm, and Torsten O. Nielsen. "Neither Tumor-Infiltrating Lymphocytes nor Cytotoxic T Cells Predict Enhanced Benefit from Chemotherapy in the DBCG77B Phase III Clinical Trial." Cancers 14, no. 15 (August 5, 2022): 3808. http://dx.doi.org/10.3390/cancers14153808.
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Recent studies have shown that immune infiltrates in the tumor microenvironment play a role in response to therapy, with some suggesting that patients with immunogenic tumors may receive increased benefit from chemotherapies. We evaluated this hypothesis in early breast cancer by testing the interaction between immune biomarkers and chemotherapy using materials from DBCG77B, a phase III clinical trial where high-risk premenopausal women were randomized to receive chemotherapy or no chemotherapy. Tissue microarrays were evaluated for tumor-infiltrating lymphocytes (TILs) assessed morphologically on hematoxylin and eosin-stained slides, and by immunohistochemistry for CD8, FOXP3, LAG-3, PD-1 and PD-L1. Following REMARK reporting guidelines, data analyses were performed according to a prespecified statistical plan, using 10-year invasive disease-free survival as the endpoint. Differences in survival probabilities between biomarker groups were evaluated by Kaplan–Meier and Cox proportional hazard ratio analyses and prediction for treatment benefit by an interaction test. Our results showed that stromal TILs were associated with an improved prognosis (HR = 0.93; p-value = 0.03), consistent with previous studies. However, none of the immune biomarkers predicted benefit from chemotherapy in the full study set nor within major breast cancer subtypes. Our study indicates that primary tumors with higher immune infiltration do not derive extra benefit from cyclophosphamide-based cytotoxic chemotherapy.
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Gyorffy, Balazs. "Abstract P4-07-20: Survival analysis using the entire transcriptome to pinpoint biomarkers with the highest prognostic power." Cancer Research 82, no. 4_Supplement (February 15, 2022): P4–07–20—P4–07–20. http://dx.doi.org/10.1158/1538-7445.sabcs21-p4-07-20.
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Abstract Introduction. Extensive research is directed to uncover new biomarkers capable to stratify breast cancer patients into clinically relevant cohorts. However, the overall performance ranking of such marker candidates compared to other genes is virtually absent. Here, we present the ranking of all survival related genes in chemotherapy treated basal and estrogen positive/HER2 negative breast cancer. Methods. We searched the GEO repository to uncover transcriptomic datasets with available follow-up and clinical data. After quality control and normalization, samples entered an integrated database. Molecular subtypes were designated using gene expression data. Survival analysis was performed using Cox proportional hazards regression. False discovery rate was computed to combat multiple hypothesis testing. Kaplan-Meier plots were drawn to visualize the best performing genes. Results. The entire database includes 7,830 unique samples from 55 independent datasets. Of those with available relapse-free survival time, 3,382 samples were estrogen receptor-positive and 696 were basal. In chemotherapy treated ER positive/ERBB2 negative patients the significant prognostic biomarker genes achieved hazard rates between 1.76 and 3.33 with a p value below 5.8E-04. The significant prognostic genes in adjuvant chemotherapy treated basal breast cancer samples reached hazard rates between 1.88 and 3.61 with a p value below 7.2E-04. Finally, an online accessible platform utilizing the entire database was set up enabling the validation of future biomarker candidates. Conclusions. A reference ranking for all genes in two chemotherapy treated breast cancer cohorts is presented. The results help to neglect those with unlikely clinical significance and to focus future research on the most promising candidates. Citation Format: Balazs Gyorffy. Survival analysis using the entire transcriptome to pinpoint biomarkers with the highest prognostic power [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-07-20.
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Chen, Yuxiao, Rui Zhu, Min Chen, Wenna Guo, Xin Yang, Xin-Jian Xu, and Liucun Zhu. "Prognostic Value of a Three-DNA Methylation Biomarker in Patients with Soft Tissue Sarcoma." Journal of Oncology 2020 (May 15, 2020): 1–11. http://dx.doi.org/10.1155/2020/8106212.
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Soft tissue sarcomas (STS) are a highly aggressive and heterogeneous group of malignant mesenchymal tumors. The prognosis of patients with advanced or metastatic STS remains poor, and the main therapy of STS patients combines primary surgery, radiotherapy, and chemotherapy. Aberrant DNA methylation shows close association with the pathogenesis and tumor progression. Therefore, DNA methylation biomarkers might have the potential in accurately predicting the survival of STS patients. In order to identify a prognostic biomarker based on DNA methylation sites, a comprehensive analysis of the DNA methylation profile of STS patients in the Cancer Genome Atlas (TCGA) database was performed. All samples were randomly divided into training and testing datasets. Cox proportional hazards regression analysis was performed to identify a prognostic biomarker that contains three DNA methylation sites. The Kaplan–Meier analysis demonstrated that the 3-DNA methylation biomarker discriminated patients into high-risk and low-risk groups, both in the training and in the testing datasets, and the area under the receiver operating characteristic curve values (AUCs) were 0.844 (P<0.001, 95% CI: 0.740–0.948) and 0.710 (P=0.002, 95% CI: 0.595–0.823), respectively. Besides, this biomarker presented superior prognostic performance in STS patients with different age, sex, tissue of origin, therapy, and histologic subtypes. Compared with other prognostic biomarkers, this biomarker tended to be a more precise prognostic factor in STS patients. Moreover, methylation sites in this biomarker might provide a new way for clinicians to make decisions regarding the intervention and assess the effectiveness of an individual therapeutic strategy.
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Tsao, Anne S., Nusrat Harun, Junya Fujimoto, Vikki Devito, J. Jack Lee, Reza J. Mehran, Waun Ki Hong, Milind B. Suraokar, and Ignacio I. Wistuba. "Elevated PDGFRB gene copy number gain as prognostic in resected malignant pleural mesothelioma." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 7078. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.7078.
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7078 Background: PDGF/PDGFR pathway has been implicated in malignant pleural mesothelioma (MPM) carcinogenesis. We sought to evaluate the incidence of PDGFRB gene copy number gain (CNG) and PDGFR pathway protein expression by immunohistochemistry (IHC) in the tumor cell cytoplasm, membrane, nucleus, and stroma, and correlate it to patient clinical outcome. Methods: 88 archived tumor blocks from resected MPM with full clinical information were used to perform the analyses. IHC biomarkers for PDGFRα,β and p-PDGFRβ, and fluorescence in situ hybridization were performed for analysis of PDGFRB gene CNG. Spearman’s rank correlation, Wilcoxon rank-sum test or Kruskal-Wallis test, BLiP plots, and Kaplan-Meier method were used to assess the biomarkers and their correlation to clinical outcome. Results: There were several correlations identified between the IHC biomarkers; however, none associated with patient demographics or histology subtype, with the exception of high cytoplasmic PDGFRα occurring in patients with no prior known asbestos exposure (p=0.029). In the CNG analysis, PDGFRB gene CNG in > 10% of tumor cells had lower cytoplasmic p-PDGFRβ (p=0.029), while PDGFRB gene CNG in > 40% of tumor cells had a higher cytoplasmic PDGFRβ (p=0.04). PDGFRB gene CNG status did not associate with patient demographics or tumor characteristics. Patients with PDGFRB CNG > 40% of tumor cells had an improved relapse-free survival (RFS) [HR 0.25 (95% CI 0.09, 0.72), p=0.0096]. In the patients with PDGFRB CNG > 40% of cells, the addition of chemotherapy appeared to also improve RFS (p=0.017). In the multi-covariate analyses for RFS, there was no association with any IHC biomarker. In the overall survival (OS) analysis, having PDGFRB gene CNG > 40% of tumor cells correlated with an improved OS [HR 0.32 (95% CI 0.11, 0.89), p=0.029] and the addition of peri-operative chemotherapy led to a trend towards improved OS (p=0.089). Conclusions: PDGFRB CNG > 40% of tumor cells is a potential prognostic biomarker in surgically resected MPM tumors. Adding chemotherapy to patients with PDGFRB CNG > 40% of cells improved RFS and led to a trend towards improved OS. Future validation of this biomarker in prospective trials is needed.
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Sasatomi, Teruo, Yutaka Ogata, Hideaki Yamana, Yoshito Akagi, and Kazuo Shirouzu. "Immunological effects as a biomarker of chemotherapy in metastatic colorectal cancer." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): e14077-e14077. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.e14077.
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e14077 Background: Many multiple anti cancer drugs regimens have been established for metastatic colorectal cancer recently. We investigated cellular immunoreaction of these patients to their cancer. Methods: 26 metastatic colorectal cancer patients have been started chemotherapies. Their PBMC were harvested and investigated their character by Fac scan with fluorescent labeled antibodies (CD3, CD8, CD4, CD25, Foxp3) at before and after chemotherapy. Results: After chemotherapy, both CTLs (CD3, CD8 positive) and regulatory T cells (CD4, CD25, Foxp3 positive) were decreased in number among all patients. On the other hand, CTL/T reg ratio were significantly increased among tumor marker decreased patients and significantly decreased among tumor marker increased or stable patients. CEA levels among 85.7% of increased CTL/T reg ratio patients became to decrease less than half. CEA levels among 66.7% of decreased CTL/T reg ratio patients became to increase or to be stable, if their regimens have not been changed. The Reactive Rate of chemotherapy of CTL/T reg ratio increased patients was significantly higher than that of ratio decreased patients. (p=0.021) The Disease Control Rate of chemotherapy of CTL/T reg ratio increased patients was higher than that of ratio decreased patients. Conclusions: We found that the CTL/T reg ratio of PBMC in metastatic colorectal cancer patients were useful for prediction of the effect of chemotherapy.
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Jongeneel, Gabrielle, Marjolein J. E. Greuter, Felice N. van Erning, Miriam Koopman, Geraldine R. Vink, Cornelis J. A. Punt, and Veerle M. H. Coupé. "Model-based effectiveness and cost-effectiveness of risk-based selection strategies for adjuvant chemotherapy in Dutch stage II colon cancer patients." Therapeutic Advances in Gastroenterology 14 (January 2021): 175628482199571. http://dx.doi.org/10.1177/1756284821995715.
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Background: We aimed to evaluate the cost-effectiveness of risk-based strategies to improve the selection of surgically treated stage II colon cancer (CC) patients for adjuvant chemotherapy. Methods: Using the ‘Personalized Adjuvant TreaTment in EaRly stage coloN cancer’ (PATTERN) model, we evaluated five selection strategies: (1) no chemotherapy, (2) Dutch guideline recommendations assuming observed adherence, (3) Dutch guideline recommendations assuming perfect adherence, (4) biomarker mutation OR pT4 stage strategy in which patients with MSS status combined with a pT4 stage or a mutation in BRAF and/or KRAS receive chemotherapy assuming perfect adherence and (5) biomarker mutation AND pT4 stage strategy in which patients with MSS status combined with a pT4 stage tumor and a BRAF and/or KRAS mutation receive chemotherapy assuming perfect adherence. Outcomes were number of CC deaths per 1000 patients and total discounted costs and quality-adjusted life-years (QALYs) per patient (pp). Analyses were conducted from a societal perspective. The robustness of model predictions was assessed in sensitivity analyses. Results: The reference strategy, that is, no adjuvant chemotherapy, resulted in 139 CC deaths in a cohort of 1000 patients, 8.077 QALYs pp and total costs of €22,032 pp. Strategies 2–5 were more effective (range 8.094–8.217 QALYs pp and range 118–136 CC deaths per 1000 patients) and more costly (range €22,404–€25,102 pp). Given a threshold of €50,000/QALY, the optimal use of resources would be to treat patients with either the full adherence strategy and biomarker mutation OR pT4 stage strategy. Conclusion: Selection of stage II CC patients for chemotherapy can be improved by either including biomarker status in the selection strategy or by improving adherence to the Dutch guideline recommendations.
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Fong, Caroline YK, and Ian Chau. "Harnessing biomarkers of response to improve therapy selection in esophago-gastric adenocarcinoma." Pharmacogenomics 22, no. 11 (July 2021): 703–26. http://dx.doi.org/10.2217/pgs-2020-0090.
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Advanced esophago-gastric (OG) adenocarcinomas have a high mortality rate and new therapeutic options are urgently required. Despite recent advances in understanding the molecular characteristics of OG cancers, tumor heterogeneity poses a challenge in developing new therapeutics capable of improving patient outcomes. Consequently, chemotherapy remains the mainstay of systemic treatment, with the HER2 being the only predictive biomarker routinely targeted in clinical practice. Recent data indicate that immunotherapy will be incorporated into first-line chemotherapy, but further research is required to refine patient selection. This review will summarize the clinical strategies being evaluated to utilize our knowledge of predictive biomarkers with reference to novel therapeutics, and discuss the barriers to implementing precision oncology in OG adenocarcinoma.
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Goggi, Julian L., Shivashankar Khanapur, Siddesh V. Hartimath, Boominathan Ramasamy, Peter Cheng, Hui-Xian Chin, Jun-Rong Tang, You-Yi Hwang, and Edward G. Robins. "Imaging Effector Memory T-Cells Predicts Response to PD1-Chemotherapy Combinations in Colon Cancer." Biomedicines 10, no. 10 (September 20, 2022): 2343. http://dx.doi.org/10.3390/biomedicines10102343.
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Often, patients fail to respond to immune checkpoint inhibitor (ICI) treatment despite favourable biomarker status. Numerous chemotherapeutic agents have been shown to promote tumour immunogenicity when used in conjunction with ICIs; however, little is known about whether such combination therapies lead to a lasting immune response. Given the potential toxicity of ICI–chemotherapy combinations, identification of biomarkers that accurately predict how individuals respond to specific treatment combinations and whether these responses will be long lasting is of paramount importance. In this study, we explored [18F]AlF-NOTA-KCNA3P, a peptide radiopharmaceutical that targets the Kv1.3 potassium channel overexpressed on T-effector memory (TEM) cells as a PET imaging biomarker for lasting immunological memory response. The first-line colon cancer chemotherapies oxaliplatin and 5-fluorouracil were assessed in a syngeneic colon cancer model, either as monotherapies or in combination with PD1, comparing radiopharmaceutical uptake to memory-associated immune cells in the tumour. [18F]AlF-NOTA-KCNA3P reliably separated tumours with immunological memory responses from non-responding tumours and could be used to measure Kv1.3-expressing TEM cells responsible for durable immunological memory response to combination therapy in vivo.
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Hynninen, Johanna, Annika Auranen, Kirsti Dean, Maija Lavonius, Olli Carpen, Antti Perheentupa, Marko Seppänen, and Seija Grénman. "Serum HE4 Profile During Primary Chemotherapy of Epithelial Ovarian Cancer." International Journal of Gynecologic Cancer 21, no. 9 (November 2011): 1573–78. http://dx.doi.org/10.1097/igc.0b013e3182225509.
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ObjectiveHuman epididymis protein 4 (HE4) is a promising novel serum biomarker for the detection of early-stage epithelial ovarian cancer (EOC) and for the differential diagnosis between benign and malignant ovarian tumors. The objective of the present study was to determine the value of HE4 for monitoring the response to primary therapy in patients with advanced disease.MethodsSerum HE4 and cancer antigen (CA) 125 levels of 10 patients with advanced EOC and one patient with adenocarcinoma of unknown origin were measured preoperatively and during first-line chemotherapy. Seven patients were treated with primary surgery and six cycles of chemotherapy. Response to treatment was evaluated 4 weeks after the completion of chemotherapy using computed tomography. Four patients received neoadjuvant chemotherapy (NACT) before surgery. To evaluate the early response to chemotherapy, changes in serum biomarker levels were compared with metabolic changes of tumors during NACT as detected by positron emission tomography/computed tomography.ResultsThe profile of HE4 during primary chemotherapy was in line with radiologic and clinical responses. In the neoadjuvant chemotherapy group, HE4 correlated better with the radiologic response than CA 125.ConclusionAssessment of serum HE4 may improve the reliability of response evaluation during chemotherapy for serous epithelial ovarian cancer.
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Wang, Yi-Zarn, Jean P. Carrasquillo, Alexis Carimi, Elizabeth McCord, Maria M. Chester, Robert Ramirez, J. Philip Boudreaux, Eugene Woltering, Daniel Raines, and Lowell Brian Anthony. "In vitro chemotherapy profiling of well-differentiated midgut neuroendocrine tumors (NETs) based on individual patient tumor biomarkers analysis." Journal of Clinical Oncology 32, no. 3_suppl (January 20, 2014): 235. http://dx.doi.org/10.1200/jco.2014.32.3_suppl.235.
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235 Background: Midgut neuroendocrine tumors (NETs) are rare malignancies with indolent clinical courses. In general, they are well differentiated with most tumor cells in the G0 phase of the cell cycle, consistent with the poor response rate of NETs to chemotherapy in vivo. We hypothesize that insults, such as surgery, can drive NET cells from G0 into S phase and that biomarker analysis of individual patient tumors harvested and grown in the lab will provide useful practical guide for future intra and post operative adjuvant therapy. Methods: 97 well-differentiated midgut NET patients underwent cytoreductive surgery at our institution between 5/2012 and 10/2012. 148 surgical specimens were collected and submitted to a single commercial lab for processing. Primary tumors, lymph nodes and liver metastases were harvested and cultured. Their RNAs were then extracted to analyze the expressivity a total of 88 different biomarkers. Based on our patients specific tumor biomarker expressivity and known correlations between 36 anti-neoplastic agents with their linked biomarkers, recommendations were reported as clinically benefit or lacking such benefit. Results: A total of 148 specimens from 97 patients were tested. In four of the 97 patients, no clinically beneficial chemotherapy agent could be identified. Among the remaining 93 patients, the top three agents that are most likely to be clinically beneficial are: Fluorouracil, Cisplatin and Carboplatin. These were reported to be clinically beneficial in 135/148 (91.2%), 103/148 (69.6%), and 103/148 (69.6%) patients respectively. Conclusions: Midgut NETs are slow growing tumors which are chemotherapeutically inert owing to the fact that most of the tumor cells are in G0 cell cycle. Surgical insult drives NET cells into active synthetic phase where they begin to express biomarkers specific to their tumor cells. Analysis of these biomarkers guides further potential beneficial therapy based on the current known associations among biomarkers and chemotherapy agents. These results must then be compared and confirmed against a direct in-vitro chemo sensitivity assessment conducted simultaneously on the same patients.
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Garcia-Carbonero, Nuria, Javier Martinez-Useros, Weiyao Li, Alberto Orta, Nuria Perez, Cristina Carames, Tatiana Hernandez, Irene Moreno, Gloria Serrano, and Jesus Garcia-Foncillas. "KRAS and BRAF Mutations as Prognostic and Predictive Biomarkers for Standard Chemotherapy Response in Metastatic Colorectal Cancer: A Single Institutional Study." Cells 9, no. 1 (January 15, 2020): 219. http://dx.doi.org/10.3390/cells9010219.
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KRAS mutation is a confirmed predictive biomarker for anti-EGFR monoclonal antibody therapy response for metastatic colorectal cancer. However, its prognosis impact and the predictive potential for first-line standard chemotherapy remains unclear. On the other hand, V600E mutation is the most frequent and studied mutation in the BRAF gene, and it has been associated with a poor outcome of patients and a low response to anti-EGFR treatment. Thus, the aim of this study is to evaluate the role of KRAS and BRAF mutations as prognosis factors and predictive biomarkers for 1st line standard chemotherapy in metastatic colorectal cancer. KRAS mutations and BRAF V600E mutations exhibited a poor outcome (p = 0.021 and p < 0.0001, respectively). Cox multivariate analysis showed that the presence of liver metastasis (HR = 1.595; 95% CI: 1.086–2.343; p = 0.017), KRAS mutation (HR = 1.643; 95% CI: 1.110–2.431; p = 0.013) and BRAF V600E mutation (HR = 5.861; 95% CI: 2.531–13.570; p < 0.0001) were statistically significant co-variables for progression-free survival. Interestingly, patients with KRAS mutations were associated with a poor response to first line standard chemotherapy (p = 0.008). In contrast, the BRAF V600E mutation did not have any impact on the first line standard chemotherapy response (p = 0.540). Therefore, in the present study, we provide new insight on the role of KRAS and BRAF, not only as prognosis biomarkers, but also as first line standard chemotherapy response biomarkers in metastatic colorectal cancer.
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Mehta, Anurag, Nayana N. Sriramanakoppa, Poojan Agarwal, Gayatri Viswakarma, Smreti Vasudevan, Manoj Panigrahi, Dushyant Kumar, et al. "Predictive biomarkers in nonsmall cell carcinoma and their clinico-pathological association." South Asian Journal of Cancer 08, no. 04 (October 2019): 250–54. http://dx.doi.org/10.4103/sajc.sajc_373_18.
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Abstract Background: Lung cancer is the leading cause of cancer-related mortality worldwide. Genome-directed therapy is less toxic, prolongs survival and provides a better quality of life. Predictive biomarker testing, therefore, has become a standard of care in advanced lung cancers. The objective of this study was to relate clinical and pathological features, including response to targeted therapy (TT) and progression-free survival (PFS) with positive driver mutation. Materials and Methods: Archival data of nonsmall cell carcinoma patients with Stage IV disease were retrieved. Those who tested positive for one of the four biomarkers (epidermal growth factor receptor [EGFR], anaplastic lymphoma kinase [ALK], MET, and ROS) were included. Patient demographics and clinical features were reviewed. Tumor histomorphology was correlated with oncological drivers. Treatment response, PFS, and overall survival were studied in three subcohorts of patients who received computed tomography (CT), CT followed by TT and those who received TT in the first line. Results: A total of 900 patients underwent biomarker evaluation of which 288 tested positive. Frequency of the four biomarkers observed was 26.6% (229/860), 6.6% (51/775), 6.6% (5/75), and 5.1% (3/59) for EGFR, ALK, MET, and ROS-1, respectively. The median PFS for EGFR-mutated cohort was 12 months, whereas it was 21 months for ALK protein overexpressing cases. Patients treated with first-line tyrosine kinase inhibitors performed better compared to those who were switched from chemotherapy to TT or those who received chemotherapy alone (P < 0.05). Conclusion: Biomarker testing has improved patient outcome. Genome-directed therapy accords best PFS with an advantage of nearly 10 months over cytotoxic therapy.