ABSTRACT
Introduction: Interleukin 17 (IL-17) has a key role in inflammatory responses. Increased serum concentrations of IL-17 have been reported in patients with different types of cancer. Some studies suggest antitumor activity of IL-17 while others speak in favor of its association with poorer prognosis. The lack of data on IL-17 behavior in vivo hinders the efforts to clarify the exact role of IL-17 in breast cancer patients and precludes the usage of IL-17 as potential therapeutic target. Methods: The study included 118 patients with early invasive breast cancer. The serum concentration of IL-17A was measured before surgery and during adjuvant treatment and compared with healthy controls. The correlation of serum IL-17A concentration and different clinical and pathological parameters, including IL-17A expression in the corresponding tumor tissue samples, was analyzed. Results: Significantly higher serum concentrations of IL-17A were found in women with early breast cancer before surgery, but also during adjuvant treatment in comparison to healthy controls. No significant correlation to tumor tissue IL-17A expression was observed. There was a significant postoperative decrease of serum IL-17A concentrations even in patients with relatively lower preoperative values. A significant negative correlation was found between serum IL-17A concentrations and the tumor estrogen receptor expression. Conclusion: The results suggest that the immune response in early breast cancer is mediated by IL-17A, particularly in triple-negative breast cancer. IL-17A-mediated inflammatory response subsides postoperatively, but IL-17A concentrations remain elevated compared to the values in healthy controls, even after the removal of the tumor.
ABSTRACT
BACKGROUND: Gastric cancer (GC) is the eighth most common cause of cancer deaths in Croatia and one of the most common causes of cancer deaths worldwide. A reliable diagnostic tool for the early detection of GC is essential. OBJECTIVE: We previously suggested a pepsinogen test method to reduce the mortality from GC by allowing early detection. Here, we report an updated analysis from a prospective single-center clinical study to evaluate the sensitivity and specificity of the pepsinogen test method and to determine whether this test can be used as a part of routine laboratory assessment of high-risk patients. METHODS: We present mature data of the pepsinogen test method in the Croatian population after a median follow-up of 36 months. Statistical analyses were performed using a Mann-Whitney U test, multiple logistic regression, and receiver operating characteristics (ROC) to evaluate the predictive power of the assayed biomarkers. RESULTS: Of the 116 patients, 25 patients had GC and 91 demonstrated a nonmalignant pathology based on tissue biopsy. Cutoff values were pepsinogen I ⩽70 and pepsinogen I/II ratio ⩽3.0. Using ROC curve analysis, the accuracy, sensitivity, specificity, positive predictive value, and negative predictive value were determined to be 87.22%, 78.12%, 90.10%, 71.43%, and 92.86%, respectively, for the diagnosis of GC. The area under the curve was 0.700 (95% confidence interval 0.57-0.83). CONCLUSION: Pepsinogen tests are valuable for screening a population in need of further diagnosis and could help to avoid unnecessary invasive endoscopic procedures.
Subject(s)
Pepsinogen A , Pepsinogen C , Stomach Neoplasms , Humans , Pepsinogen A/blood , Pepsinogen C/blood , Prospective Studies , Sensitivity and Specificity , Stomach Neoplasms/diagnosis , Stomach Neoplasms/pathologyABSTRACT
Breast cancer is the most common malignancy in females. Despite its well-established prognostic factors, our prognostic ability at an individual patient level remains limited. In this study, the immunohistochemical expression of B-Myb and DNA topoisomerase 2-alpha (Topo2a) was analyzed in primary tumors to identify patients with a higher risk of disease recurrence after adjuvant chemotherapy for early invasive breast cancer. We analyzed a cohort of 215 early invasive breast cancer patients having undergone surgery from 2002 to 2003 at the Zagreb University Hospital Centre, including 153 patients treated with adjuvant chemotherapy. All of them were followed-up prospectively for at least ten years according to routine institutional practice. Statistically significant correlations were found between B-Myb and Topo2a expression levels and particular well-established prognostic factors. B-Myb expression was lower in estrogen receptor (ER)-positive tumors (p=0.0773), whereas larger tumors and those with positive lymphovascular invasion displayed a statistically significantly higher B-Myb expression (p=0.0409 and p=0.0196). Higher tumor grade indicated higher Topo2a values (p=0.0102 and p=0.0069). The subgroup with the expression of both proteins above the median value had an almost statistically significantly (p=0.0613) inferior prognosis compared to the rest of the cohort. Study results showed the B-Myb and Topo2a expression to have a prognostic value in breast cancer patients after adjuvant chemotherapy, which should be additionally explored in future studies in a larger patient cohort.
Subject(s)
Breast Neoplasms , Breast Neoplasms/drug therapy , Chemotherapy, Adjuvant , DNA Topoisomerases, Type II/therapeutic use , Female , Humans , Neoplasm Recurrence, Local , Prognosis , Receptor, ErbB-2ABSTRACT
BACKGROUND: Apoptosis inhibition is a major tumorigenic factor. Bcl-2 dysregulation and TP53 mutation status, which may correlate with autoantibody generation, contribute to impaired apoptosis. OBJECTIVE: This study aimed to investigate the prognostic value of circulating Bcl-2 and anti-p53 antibodies (p53Abs) in a 17.5-year follow-up of breast cancer patients. We also analyzed the correlations of Bcl-2 and p53Abs with various clinicopathological parameters in order to assess their impact on tumor aggressiveness. METHODS: Serum Bcl-2 and p53Abs levels were analyzed by the enzyme-linked immunosorbent assay (ELISA) in 82 patients with invasive breast cancer and twenty individuals without malignancy. RESULTS: Serum Bcl-2 and p53Abs levels in breast cancer patients were significantly higher than those in controls. Patients with high levels of Bcl-2 (cut-off 200 U/ml) had a poorer prognosis (17.5-year survival) than those with lower Bcl-2 values. In combined analysis the subgroup of patients with elevated p53Abs (cut-off 15 U/ml) and elevated Bcl-2 (cut-offs 124 U/ml and 200 U/ml) had the worse prognosis in 17.5-year survival. In correlation analysis p53Abs and Bcl-2 were associated with unfavorable clinicopathological parameters. CONCLUSIONS: Our results suggest that breast cancer patients with high serum levels of p53Abs and Bcl-2 present an especially unfavorable group in a long follow-up.
Subject(s)
Breast Neoplasms/genetics , Proto-Oncogene Proteins c-bcl-2/metabolism , Tumor Suppressor Protein p53/metabolism , Breast Neoplasms/pathology , Female , Follow-Up Studies , Humans , Middle Aged , PrognosisABSTRACT
Triple-negative breast cancer (TNBC) occurs in around one-sixth of all breast cancer (BC) patients, with the most aggressive behavior and worst prognosis of all BC subtypes. It is a heterogeneous disease, with specific molecular characteristics and natural dynamics of early recurrence and fast progression. Due to the lack of biomarkers or any valid treatment targets, it can only be treated with classic cytotoxic chemotherapy. We analyzed a cohort of 152 patients, median age 58 years, diagnosed with and treated for early stage TNBC at the University Hospital for Tumors, Sestre milosrdnice University Hospital Centre, Zagreb, Croatia, during the 2009-2012 period. Patients were treated with primary surgical approach, adjuvant chemotherapy and adjuvant irradiation. We observed a relatively large proportion of locally advanced TNBC at diagnosis, with large tumor size and nodal involvement, with high grade and high proliferation index Ki67. Patient age, tumor size and lymph node involvement, as expected, were significant and clinically most important prognostic factors for 5-year disease-free survival (67%; 95% CI 60%-75%) and overall absolute survival rate (74%; 95% CI 66%-81%).
Subject(s)
Breast Neoplasms , Triple Negative Breast Neoplasms , Breast Neoplasms/diagnosis , Breast Neoplasms/therapy , Croatia/epidemiology , Disease-Free Survival , Female , Humans , Middle Aged , Prognosis , Retrospective Studies , Triple Negative Breast Neoplasms/epidemiology , Triple Negative Breast Neoplasms/therapyABSTRACT
Coronavirus disease 2019 (COVID-19) is an infectious disease caused by a new virus that has never been identified in humans before. COVID-19 caused at the time of writing of this article, 2.5 million cases of infections in 193 countries with 165,000 deaths, including two-third in Europe. In this context, Oncology Departments of the affected countries had to adapt quickly their health system care and establish new organizations and priorities. Thus, numerous recommendations and therapeutic options have been reported to optimize therapy delivery to patients with chronic disease and cancer. Obviously, while these cancer care recommendations are immediately applicable in Europe, they may not be applicable in certain emerging and low- and middle-income countries (LMICs). In this review, we aimed to summarize these international guidelines in accordance with cancer types, making a synthesis for daily practice to protect patients, staff and tailor anti-cancer therapy delivery taking into account patients/tumour criteria and tools availability. Thus, we will discuss their applicability in the LMICs with different organizations, limited means and different constraints.
Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/prevention & control , Infection Control/organization & administration , Medical Oncology/organization & administration , Neoplasms/therapy , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Practice Guidelines as Topic , COVID-19 , Coronavirus Infections/epidemiology , Coronavirus Infections/transmission , Coronavirus Infections/virology , Developing Countries/economics , Global Burden of Disease , Humans , Infection Control/economics , Infection Control/standards , Medical Oncology/economics , Medical Oncology/standards , Neoplasms/diagnosis , Pneumonia, Viral/epidemiology , Pneumonia, Viral/transmission , Pneumonia, Viral/virology , Poverty , SARS-CoV-2ABSTRACT
We have previously demonstrated the nucleic acid binding capacity of phenanthridine derivatives (PHTs). Because nucleic acids are potent inducers of innate immune response through Toll-like receptors (TLRs), and because PTHs bear a structural resemblance to commonly used synthetic ligands for TLR7/8, we hypothesized that PHTs could modulate/activate immune response. We found that compound M199 induces secretion of IL-6, IL-8 and TNFα in human PBMCs and inhibits TLR3/9 activation in different cellular systems (PBMCs, HEK293 and THP-1 cell lines).
Subject(s)
Immunologic Factors/pharmacology , Phenanthridines/pharmacology , Toll-Like Receptor 3/metabolism , Toll-Like Receptor 9/metabolism , Urea/analogs & derivatives , Urea/pharmacology , Cell Line , Down-Regulation , Humans , Intercalating Agents/pharmacology , Interferon-alpha/genetics , Interferon-alpha/metabolism , Interleukin-6/genetics , Interleukin-6/metabolism , Interleukin-8/genetics , Interleukin-8/metabolism , Oligodeoxyribonucleotides/pharmacology , Signal Transduction , Tumor Necrosis Factor-alpha/metabolismABSTRACT
BACKGROUND: Unexpected differences in Ki-67 values among HER2 & ER/PgR defined subgroups were found. This study aims to detect possible subdivisions beyond the conventional breast cancer types. METHODS: One thousand one hundred eighty consecutive patients with invasive ductal breast carcinoma were included and distributed in 16 subgroups (four HER2 phenotypes (0+, 1+, 2+ and 3+) times four ER/PgR phenotypes). Complex distributions of Ki-67 values were tested by expectation maximization (EM) clustering. RESULTS: Pooled Ki67 values of all patients showed the presence of three EM clusters (defined as LMA-low mitotic activity, IMA-intermediate mitotic activity and HMA-high mitotic activity) with expected mean Ki-67 values of 1.17%, 40.45% and 77.79%, respectively. Only ER-PgR- tumors significantly dispersed in three clusters (29.75% tumors in LMA, 46.95% in IMA and 23.30% in the HMA cluster), while almost no detected HMA tumors were of ER + PgR+ or ER + PgR- phenotypes. Among 799 ER + PgR+ patients distribution in clusters was HER2 dependent (p = 0.000243), due to increased number of IMA HER2 3+ tumors on the expense of LMA HER2 3+ tumors (52 IMA out of 162 HER2 3+ patients versus113 IMA out of 637 HER2 < 3+ patients). This was not found among ER + PgR- patients (p = 0.186968). Among ER-PgR- patients, HER2 overexpression also increased number of IMA tumor, but by reducing the number of HMA tumors (p < 0.000001). Here, difference between HER2 absent (0+) and HER2 3+ patients was evident (10 HMA out of 125 HER2 3+ patients versus 42 HMA out of 103 HER2 0+ patients). CONCLUSIONS: Results suggest that distributions of breast cancers in three clusters of mitotic activity depend on different mechanisms for ER + PgR+ and ER negative tumors. Although HER2 overexpression increases number of IMA tumors in both settings, in the former it is done by reducing number of LMA tumors, while in the latter it reduces the number of HMA tumors. Mitotic activity of ER + PgR- tumors seems unrelated to the HER2 status, possibly as an indicator that ER dysfunctionality in cancers that lack PgR expression. Among ER negative tumors, the absence of HER2 (0+) might be as important as the HER2 overexpression.
Subject(s)
Breast Neoplasms , Carcinoma, Ductal, Breast , Ki-67 Antigen/analysis , Receptor, ErbB-2/metabolism , Receptors, Estrogen/metabolism , Breast Neoplasms/classification , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Carcinoma, Ductal, Breast/classification , Carcinoma, Ductal, Breast/metabolism , Carcinoma, Ductal, Breast/pathology , Female , Humans , Immunohistochemistry , Ki-67 Antigen/metabolism , Receptor, ErbB-2/analysis , Receptors, Estrogen/analysisABSTRACT
Treatment of oncological patients must be based upon multidisciplinary approach, and takes place in specialized oncological centers. By the end of a specific oncological treatment further follow-up is being managed mostly by the oncologists, but the role of the general practitioners becomes more important every day and therefore should be precisely defined. Nowadays, most of the existing follow-up guidelines are not being based on prospective studies, yet on the expert's opinion of a precise oncological center or specialists. The aim of the Croatian Society of Medical Oncology (CSMO) with these recommendations is to standardize and rationalize the diagnostic procedures' algorithm in followup of oncological patients after primary treatment, in patients with planocellular head and neck cancer, oesophageal cancer, gastric cancer and colorectal cancer.
Subject(s)
Colorectal Neoplasms , Esophageal Neoplasms , Head and Neck Neoplasms , Stomach Neoplasms , Colorectal Neoplasms/therapy , Esophageal Neoplasms/therapy , Follow-Up Studies , Head and Neck Neoplasms/therapy , Humans , Medical Oncology , Practice Guidelines as Topic , Prospective Studies , Stomach Neoplasms/therapyABSTRACT
Melanoma in the Western world has an increasing incidence. One of the most important factor for the increase in incidence is sporadic, uncontrolled exposure to the sun. The basis for the treatment of primary melanoma is surgical treatment. Treatment of metastatic disease of melanoma in recent years experienced significant changes. BRAF and MEK inhibitors, immunotherapy with programmed cell-death immune checkpoint inhibitors (anti-PD-1-antibodies) are new options for the treatment of metastatic disease. A mulitidisiplinary team of Croatian Society for Medical Oncology provides recommendations for diagnosis, treatment and follow-up of melanoma primarily driven to the discovery of new drugs and therapeutic options, that change the prognosis of patients with metastatic melanoma.
Subject(s)
Antineoplastic Agents/therapeutic use , Immunotherapy/methods , Melanoma , Surgical Procedures, Operative/methods , Croatia , Disease Management , Humans , Melanoma/diagnosis , Melanoma/pathology , Melanoma/therapy , Neoplasm Metastasis , Prognosis , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins B-raf/antagonists & inhibitorsABSTRACT
Telomerase expression is an important mechanism of tumor unlimited replicative potential. The aim of this study was to evaluate prognostic impact of telomerase activity in breast cancer patients and to correlate telomerase activity with established prognostic factors. We analyzed tissue of 102 malignant breast lesions and 20 healthy breast tissues. Telomerase activity was determined by telomeric repeat amplification protocol assay. Telomerase activity was present in 77 (75.49 %) of 102 breast cancers. Telomerase activity in breast cancers was statistically significantly higher in comparison with the activity in normal breast tissue. The levels of telomerase activity were significantly positively correlated with tumor size, axillary nodal status, histological grade, HER-2/neu protein expression in tumor tissue and expression of the nuclear antigen Ki-67. A statistically significant negative correlation was found between the presence of ER and telomerase activity. There was no correlation between telomerase activity and concentration of PR or the age of patients. Kaplan-Meier analysis showed that patients with higher telomerase activity had significantly shorter 10-year disease-free survival (p < 0.0001) and 10-year overall survival (p < 0.0001) than those with lower telomerase activity. These results were confirmed by logistic regression analysis. Our results support the prognostic role of telomerase activity and its relationship with the more aggressive phenotype of breast cancer.
Subject(s)
Breast Neoplasms/diagnosis , Breast Neoplasms/enzymology , Phenotype , Telomerase/metabolism , Adult , Biomarkers, Tumor/metabolism , Breast Neoplasms/surgery , Disease-Free Survival , Enzyme Activation/physiology , Female , Humans , Middle Aged , PrognosisABSTRACT
Treatment of oncological patients must be based upon multidisciplinary approach, and takes place in specialized oncological centers. By the end of a specific oncological treatment further follow-up is managed mostly by the oncologists, but the role of the general practitioners becomes more important every day and therefore should be precisely defined. Nowadays, most of the existing follow-up guidelines are not based on prospective studies, but on the experts opinion of a particular oncological center or specialists. The aim of the Croatian Society of Medical Oncology (CSMO) with these recommendations is to standardise and rationalise the diagnostic procedures algorithm in the follow-up of oncological patients after primary treatment.
Subject(s)
Aftercare/organization & administration , Breast Neoplasms/therapy , Genital Neoplasms, Female/therapy , Medical Oncology/organization & administration , Aftercare/standards , Breast Neoplasms/diagnosis , Croatia , Female , Genital Neoplasms, Female/diagnosis , Humans , Medical Oncology/standards , Ovarian Neoplasms/diagnosis , Ovarian Neoplasms/therapy , Practice Guidelines as Topic , Prospective Studies , Uterine Cervical Neoplasms/diagnosis , Uterine Cervical Neoplasms/therapy , Uterine Neoplasms/diagnosis , Uterine Neoplasms/therapyABSTRACT
The treatment of oncological patients must be based upon multidisciplinary approach, and takes place in specialized oncological centers. By the end of a specific oncological treatment further follow-up is being managed mostly by the oncologists, but the role of the general practitioners becomes more important every day and therefore should be precisely defined. Nowadays, most of the existing follow-up guidelines are not based on prospective studies, but on the experts opinion of individual oncological centers or specialists. The aim of the Croatian Society of Medical Oncology (CSMO) with these recommendations is to standardize and rationalize the diagnostic procedures algorithm in the followup of oncological patients after primary treatment, in patients with renal cell cancer, urinary bladder cancer, prostate cancer and testicular cancer.
Subject(s)
Aftercare/organization & administration , Medical Oncology/organization & administration , Prostatic Neoplasms/therapy , Testicular Neoplasms/therapy , Urinary Bladder Neoplasms/therapy , Aftercare/standards , Croatia , Female , Humans , Male , Medical Oncology/standards , Practice Guidelines as Topic , Prospective Studies , Prostatic Neoplasms/diagnosis , Testicular Neoplasms/diagnosis , Urinary Bladder Neoplasms/diagnosisABSTRACT
The treatment of oncological patients must be based upon multidisciplinary approach, and takes place in specialized oncological centers. By the end of a specific oncological treatment further follow-up is being managed mostly by the oncologists, but the role of the general practitioners becomes more important every day and therefore should be precisely defined. Nowadays, most of the existing follow-up guidelines are not based on prospective studies, but on the experts opinion of individual oncological centers or specialists. The aim of the Croatian Society of Medical Oncology (CSMO) with these recommendations is to standardize and rationalize the diagnostic procedures algorithm in the follow-up of oncological patients after primary treatment, in patients with neuroendocrine neoplasms, hepatocellular carcinoma, pancreatic cancer and cancer of the bile ducts.
Subject(s)
Aftercare/organization & administration , Bile Duct Neoplasms/therapy , Liver Neoplasms/therapy , Medical Oncology/organization & administration , Pancreatic Neoplasms/therapy , Aftercare/standards , Bile Duct Neoplasms/diagnosis , Carcinoma, Hepatocellular/diagnosis , Carcinoma, Hepatocellular/therapy , Carcinoma, Neuroendocrine/diagnosis , Carcinoma, Neuroendocrine/therapy , Croatia , Humans , Liver Neoplasms/diagnosis , Medical Oncology/standards , Pancreatic Neoplasms/diagnosis , Practice Guidelines as Topic , Prospective StudiesABSTRACT
BACKGROUND: Correlations between development of hand-foot syndrome (HFS) and efficacy in patients receiving capecitabine (CAP)-containing therapy are reported in the literature. We explored the relationship between HFS and efficacy in patients receiving CAP plus bevacizumab (BEV) in the TURANDOT randomised phase III trial. METHODS: Patients with HER2-negative locally recurrent/metastatic breast cancer (LR/mBC) who had received no prior chemotherapy for LR/mBC were randomised to BEV plus paclitaxel or BEV-CAP until disease progression or unacceptable toxicity. This analysis included patients randomised to BEV-CAP who received ⩾1 CAP dose. Potential associations between HFS and both overall survival (OS; primary end point) and progression-free survival (PFS; secondary end point) were explored using Cox proportional hazards analyses with HFS as a time-dependent covariate (to avoid overestimating the effect of HFS on efficacy). Landmark analyses were also performed. RESULTS: Among 277 patients treated with BEV-CAP, 154 (56%) developed HFS. In multivariate analyses, risk of progression or death was reduced by 44% after the occurrence of HFS; risk of death was reduced by 56%. The magnitude of effect on OS increased with increasing HFS grade. In patients developing HFS within the first 3 months, median PFS from the 3-month landmark was 10.0 months vs 6.2 months in patients without HFS. Two-year OS rates were 63% and 44%, respectively. CONCLUSIONS: This exploratory analysis indicates that HFS occurrence is a strong predictor of prolonged PFS and OS in patients receiving BEV-CAP for LR/mBC. Early appearance of HFS may help motivate patients to continue therapy.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/adverse effects , Breast Neoplasms/drug therapy , Hand-Foot Syndrome/etiology , Liver Neoplasms/drug therapy , Lung Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bevacizumab/administration & dosage , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Capecitabine/administration & dosage , Disease-Free Survival , Female , Humans , Liver Neoplasms/metabolism , Liver Neoplasms/secondary , Lung Neoplasms/metabolism , Lung Neoplasms/secondary , Middle Aged , Multivariate Analysis , Prognosis , Proportional Hazards Models , Receptor, ErbB-2/metabolism , Treatment OutcomeABSTRACT
Treatment of oncological patients must be based upon multidisciplinary approach, and takes place in specialized oncological centers. By the end of a speciï¬ c oncological treatment further follow-up is managed mostly by the oncologists, but the role of the general practitioners becomes more important every day and therefore should be precisely deï¬ ned. Nowadays, most of the existing follow-up guidelines are not based on prospective studies, but on the experts opinion of a particular oncological center or specialists. The aim of the Croatian Society of Medical Oncology (CSMO) with these recommendations is to standardise and rationalise the diagnostic procedures algorithm in the follow-up of oncological patients after primary treatment.
Subject(s)
Aftercare , Breast Neoplasms/therapy , Ovarian Neoplasms/therapy , Uterine Cervical Neoplasms/therapy , Uterine Neoplasms/therapy , Aftercare/methods , Aftercare/standards , Algorithms , Croatia , Female , Follow-Up Studies , Humans , Medical Oncology/methodsABSTRACT
Treatment of oncological patients must be based upon multidisciplinary approach, and takes place in specialized oncological centers. By the end of a specific oncological treatment further follow-up is being managed mostly by the oncologists, but the role of the general practitioners becomes more important every day and therefore should be precisely defined. Nowadays, most of the existing follow-up guidelines are not being based on prospective studies, yet on the expert's opinion of a precise oncological center or specialists. The aim of the Croatian Society of Medical Oncology (CSMO) with these recommendations is to standardize and rationalize the diagnostic procedures' algorithm in followup of oncological patients after primary treatment, in patients with melanoma, sarcomas, central nerve system tumors and lung cancer.
Subject(s)
Aftercare , Central Nervous System Neoplasms/therapy , Lung Neoplasms/therapy , Melanoma/therapy , Sarcoma/therapy , Aftercare/methods , Aftercare/standards , Croatia , Humans , Medical Oncology/methodsABSTRACT
BACKGROUND: This updated analysis of the CECOG/CORE 1.2.002 study investigated the association between clinical outcome and RAS and BRAF mutations in metastatic colorectal cancer (mCRC) patients treated with FOLFOX4 plus cetuximab. PATIENTS AND METHODS: Available DNA samples from CECOG/CORE 1.2.002 study patients with KRAS exon 2 wild type (wt) (at codons 12 and 13) tumors were screened for mutations at other loci in the KRAS and NRAS (RAS) coding regions by Sanger sequencing, and for BRAF codon 600 mutations by Sanger sequencing and pyrosequencing. Clinical outcome was compared among different mutation subgroups. RESULTS: Of 152 KRAS wt mCRC patients, 148 were evaluable for RAS and BRAF mutation status. Eleven RAS mutations were detected in 10 patients' tumors (7%). BRAF mutations were detected in 14 patients' tumors (9%). RAS and BRAF tumor mutations were mutually exclusive. Compared with patients with RAS wt/BRAF wt tumors (n = 124; median overall survival, 28.5 months), those with RAS mutations (n = 10; median, 16.3 months; hazard ratio, 0.43; 95% confidence interval, 0.20-0.89; P = .020) or BRAF mutations (n = 14; median, 11.7 months; hazard ratio, 0.23; 95% confidence interval, 0.12-0.41; P < .0001) had worse overall survival, which remained significant (P < .04) when adjusting for differences in baseline characteristics among the mutation subgroups. CONCLUSION: These findings support those from recent studies that RAS and BRAF mutations are associated with poor outcome in patients receiving an epidermal growth factor receptor-targeted monoclonal antibody in combination with oxaliplatin-based chemotherapy. Furthermore, mutation testing should not only include RAS codons 12 and 13 but should also be extended to the entire coding regions.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colorectal Neoplasms/drug therapy , GTP Phosphohydrolases/genetics , Liver Neoplasms/drug therapy , Membrane Proteins/genetics , Mutation/genetics , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins/genetics , ras Proteins/genetics , Aged , Cetuximab/administration & dosage , Codon/genetics , Colorectal Neoplasms/genetics , Colorectal Neoplasms/mortality , Colorectal Neoplasms/pathology , Female , Fluorouracil/administration & dosage , Follow-Up Studies , Humans , Leucovorin/administration & dosage , Liver Neoplasms/genetics , Liver Neoplasms/mortality , Liver Neoplasms/secondary , Male , Middle Aged , Neoplasm Staging , Organoplatinum Compounds/administration & dosage , Oxaliplatin , Prognosis , Proto-Oncogene Proteins p21(ras) , Retrospective Studies , Survival RateABSTRACT
BACKGROUND: Oxidative stress is thought to play a major role in etiology of many cancers, including breast cancer. 8-hydroxy-2'deoxyguanosine (8-OHdG) is the most abundant marker of oxidative DNA damage. The aim of this study was to assess the extent of oxidative DNA damage in different breast cancer molecular surrogate subtypes to investigate the prognostic relevance and role of oxidative base lesion (8-OHdG) in the etiology of breast cancer. MATERIALS AND METHODS: 8-OHdG expression was immunohistochemicaly studied on tissue microarrays constructed from 152 patients with invasive breast cancer. Expression was correlated with other prognostic factors, as well as different breast cancer molecular surrogate subtypes such as luminal A, luminal B [human epidermal growth factor receptor 2 (HER2) negative], luminal B (HER2 positive), HER2-enriched ad triple-negative tumors. RESULTS: Triple-negative breast carcinomas (TNBCs) were more frequently 8-OHdG negative compared with non-TNBCs (P=0.036). There was no statistically significant difference between 8-OHdG expression and other breast cancer molecular subtypes.In univariate analysis, there was no significant difference between 8-OHdG expression and breast cancer-specific death, although in multivariate analysis 8-OHdG overexpression was associated with better breast cancer-specific survival (BCSS) (odds ratio=0.04, 95% confidence interval, 0.002-0.62). In Cox regression analysis, patients with moderate and strong 8-OHdG expression had 0.9 times smaller breast cancer death hazard ratio than patients with negative 8-OHdG expression. CONCLUSIONS: Oxidative stress may have less impact in the pathogenesis of TNBCs compared with other surrogate breast cancer molecular subtypes. 8-OHdG may be a promising biomarker in the prediction of prognosis for breast cancer patients.