Lorlatinib experience in a patient with ALK + non-small cell lung cancer on hemodialysis: A case report.

INTRODUCTION: Lorlatinib is a potent third-generation anaplastic lymphoma kinase/c-ros oncogene 1 (ALK)/ROS1 oral tyrosine kinase inhibitor that has broad coverage of acquired resistance mutations and is currently indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are ALK-positive. CASE REPORT: In this case, we aimed to present the safety and effectiveness of lorlatinib use in a patient diagnosed with ALK-positive metastatic NSCLC who underwent hemodialysis 3 days a week. MANAGEMENT & OUTCOME: A 76-year-old female patient has been undergoing regular hemodialysis for about 2 years. A brain magnetic resonance imaging (MRI) was taken due to headache and a mass was detected. She was diagnosed with lung adenocarcinoma as a result of excisional biopsy. Positron emission tomography/ computed tomography (PET/CT) showed a mass in the hilar region of the left lung and multiple lymphadenopathy in the mediastinum. In February 2023, 100 mg lorlatinib was started daily. There was no significant regression in PET-CT and no brain MRI residue during follow-up. The patient has been continuing lorlatinib for approximately 1 year with almost complete response, with no side effects other than hypercholesterolemia. DISCUSSION: We presented our experience using lorlatinib in a patient with metastatic ALK + NSCLC undergoing hemodialysis. Although the dosage of lorlatinib in hemodialysis patients is still controversial, our case report indicates that 100 mg lorlatinib was safe in this patient.

Rare case of myelodysplastic syndrome with excess blasts 2 developing after adjuvant chemoradiotherapy for triple-negative breast cancer in a patient with Bloom syndrome.

INTRODUCTION: Bloom syndrome (BS) is a rare autosomal recessive disorder caused by a loss-of-function mutation in the BLM gene encoding an RecQ helicase involved in DNA repair and maintenance of chromosomal stability. In patients with BS, significant sensitivity to both DNA-damaging chemotherapy (CT) and ionizing radiation complicates the management of neoplasms by exacerbating comorbidities and predisposing to toxicities and poor outcomes. CASE REPORT: A 30-year-old female patient diagnosed with BS who presented with early-stage triple-negative breast cancer was treated with four cycles of doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2) followed by weekly paclitaxel (80 mg/m2) for 12 weeks as the chemotherapy protocol and a total of 5000 cGy curative radiotherapy (RT). Due to pancytopenia 8 months after completion of therapy, bone marrow biopsy and aspiration were performed, and a diagnosis of myelodysplastic syndrome with excess blasts 2 (MDS-EB2) was made. Two courses of the azacitidine (75 mg/m2) protocol were administered every 28 days in the hematology clinic. Two weeks after CT the patient was transferred from the emergency department to the hematology clinic with the diagnosis of pancytopenia and febrile neutropenia. She died at the age of 33 due to sepsis that developed during follow-up. CONCLUSION: Due to the rarity of BS, there is no prospective trial in patients with cancer and no evidence base upon which to design treatment programs. For these reasons, it is strongly recommended that patients receive multidisciplinary care, with precise assessment and discussion of the indication and an adequate dose of DNA-damaging agents such as chemotherapy and ionizing radiation.

Real-world data on the efficacy and safety of trastuzumab emtansine in patients with metastatic breast cancer previously treated with pertuzumab: Turkish oncology group multicenter study.

We aimed to evaluate the efficacy and safety of trastuzumab emtansine in patients with metastatic breast cancer previously treated with pertuzumab plus trastuzumab and taxane. We reviewed the medical records of patients who were diagnosed with Human Epidermal Growth Factor Receptor 2 (HER-2) positive metastatic breast cancer and received pertuzumab and then TDM-1 between January 2014 and January 2021 from twenty- five cancer centers. The Kaplan- Meier method estimated progression-free survival (PFS) and overall survival (OS). Additionally, objective response rate (ORR), clinical benefit rate (CBR), and safety were evaluated. One hundred fifty-three patients were included,79.1% of the patients received TDM-1 in the second line, 90.8% had visceral metastasis, and 30.7% had central nervous system involvement. The PFS and OS of TDM-1 were evaluated according to the number of previous lines (on the 2nd line or more than two lines) metastatic sites (visceral and non-visceral) and the presence of central nervous metastasis. In TDM-1 therapy, PFS in second line therapy was ten months (95% CI: 7.7 - 12.2); this was statistically higher than later-line PFS, which was six months (95% CI: 3.3 to 8.6) (p = 0.004). The median OS time was 25 months (95% CI: 21.0 to 28.9) in patients treated with TDM-1 in the second line and 19 months (95% CI: 12.3 to 25.6) in patients who received later than the second line(p = 0.175). There were no significant differences in PFS time of patients with and without visceral and central nervous metastases. Our study showed that TDM-1 was also effective in patients using pertuzumab, contributes significantly to PFS when used in the second line compared to its use in the later line, and does not make any difference in OS.

Efficacy of Systemic Treatments in Patients With Metastatic Lung Invasive Mucinous Adenocarcinoma.

BACKGROUND: Invasive mucinous adenocarcinoma (IMA) is a rare histological subtype of lung invasive adenocarcinoma with unique clinical, radiological, histopathological, and genomic characteristics. There have been limited studies on the effectiveness of systemic therapy for lung IMA, with conflicting results reported. METHODS: We retrospectively investigated the medical records of patients diagnosed with lung IMA. Patients who were ≥ 18 years of age and received at least 1 course of treatment for metastatic or locally advanced inoperable disease were included in the study. Archive records of 113 patients diagnosed with IMA were screened for the study. RESULTS: A total of 41 patients with lung IMA were included. The targetable mutation rate was 20.6% (in 6 of 29 patients). Most patients (83.1%) had received platinum-based chemotherapy as a first-line treatment. The objective response rate (ORR) was 25.7%, and median progression-free survival (PFS) and overall survival (OS) were 8.1 months (95% CI, 5.02-11.2) and 17.5 months (95% CI, 11.7-23.3 months), respectively, in the patients who received chemotherapy. The median PFS and ORR were 20.6 (95% CI, 18.9-66.5) and 66.6%, respectively, in epidermal growth factor receptor (EGFR) mutation-positive patients (n = 3) with relevant targeted therapy. Only 1 patient used oxaliplatin and capecitabine combination (XELOX) as chemotherapy in the second-line treatment and achieved a partial response (PR) at 7.2 months. CONCLUSION: Platinum-based chemotherapies moderately enhance IMA patients' survival rates. Anti-EGFR-targeted drugs are seen as potentially effective in patients with EGFR driver mutation positive. Large, prospective studies are needed to confirm our findings.

Comparison of the second-line treatment efficacy in advanced gastric cancer patients previously treated with taxane-based triplet chemotherapy: a Turkish Oncology Group Study.

OBJECTIVE: This study aimed to assess the efficacy and safety of FOLFIRI and paclitaxel in patients with advanced gastric cancer (AGC) who were previously treated with first-line modified docetaxel, cisplatin, 5-fluorouracil (mDCF), or 5-fluorouracil, oxaliplatin, docetaxel (FLOT). METHODS: Patients who received a triplet regimen in the first line setting and were treated with FOLFIRI or paclitaxel in the second-line treatment were included. RESULTS: The study included 198 patients, with 115 receiving FOLFIRI and 83 receiving paclitaxel. The median age was 58 (range = 24-69). The median progression-free survival (mPFS) was 5.2 [95% confidence interval (CI) = 4.4-5.5] months in the FOLFIRI arm, and 4.1 (95% CI = 3.3-4.6) months in the paclitaxel arm (p = .007). The median overall survival (mOS) was 9.4 (95% CI = 7.4-10.5) months in the FOLFIRI arm and 7.2 (95% CI = 5.6-8.3) months in the paclitaxel arm (p = .008). Grade 3-4 neuropathy was higher in patients receiving paclitaxel compared to those receiving FOLFIRI (p = .04). Grade 3-4 diarrhea was 8% in the FOLFIRI arm and 2.4% in the paclitaxel arm (p = .02). CONCLUSION: Beyond progression with docetaxel-based triplet chemotherapy, FOLFIRI may be preferred as a second-line treatment over paclitaxel due to its longer mPFS and mOS.

The effect of concomitant beta-blocker use on survival in patients with metastatic renal cell carcinoma treated with a vascular endothelial growth factor receptor inhibitors in the first line.

PURPOSE: Vascular endothelial growth factor (VEGF) inhibition is one of the cornerstones of treatment in the treatment of metastatic renal cell carcinoma (mRCC). Since RCC is a disease of advanced age and hypertension as a side effect of VEGF receptor inhibitors, beta-blocker use is common in these patients. We aimed to compare the treatment efficacy and survival results in case of concomitant use of these two drugs due to the inhibition of VEGF in beta-blockers. METHODS: A total of 121 patients with a diagnosis of mRCC who used sunitinib or pazopanib in first-line therapy were included in the study. These patients were divided into two groups as those using concomitant beta-blockers and those not using them. RESULT: The median overall survival (mOS) of the patient using sunitinib or pazopanib and concomitant beta-blocker was 47 (95% CI 29.0-65.0) months, and the mOS of those not using concomitant beta-blocker was 18 (95% CI 8.9-27.1) months (p < 0.001). The median progression-free survival (mPFS) of the patients using sunitinib or pazopanib and concomitant beta-blocker was 20.4 (95% CI 4.5-40.1) months, and the mPFS of those not using it was 11.4 (95% CI 5.9-16.9) months (p = 0.042). Concomitant beta-blocker use was found to be a good prognostic factor for OS in the multivariate analysis (p = 0.029). In the multivariate analysis, concomitant beta-blocker use had a trend towards statistical significance for PFS (p = 0.062). CONCLUSION: Concomitant use of betablockers with sunitinib or pazopanib is associated with longer overall survial and progression free survival.

The correlation between pre-treatment CEA levels and the EGFR mutation status in advanced lung adenocarcinoma.

BACKGROUND: The discovery of the epidermal growth factor receptor (EGFR) mutation, especially in adenocarcinoma, has led to a major change in the treatment of non-small-cell lung cancer (NSCLC). This study investigated the relationship between the EGFR mutation status and the carcinoembryonic antigen (CEA) levels at the time of diagnosis. MATERIALS AND METHODS: A total of 102 patients with EGFR mutation and tested CEA levels were recruited for this study. Of the patients, 24 were EGFR mutants (23.5%), while 78 patients (76.5%) did not harbor any EGFR mutations. RESULTS: The CEA levels did not differ across groups. Additionally, the CEA levels were analyzed between female and male patients separately due to EGFR mutations; no difference was observed. When the CEA levels were categorized as positive or negative based on different cut-off values, such as 5 and 10 ng/ml, no statistical difference was found between groups. CONCLUSION: In this study, no relationship between EGFR mutation and pre-treatment CEA levels was observed. Despite positive trials having shown a predictive value of CEA levels for EGFR mutation, more clinical trials are needed to elucidate the racial, clinical, and pathological differences of the study populations. Most studies have been located in the Far East, but new trials in Caucasian, African, and Hispanic populations are still lacking.

PROPSEA, safety evaluation of palbociclib and ribociclib in older patients with breast cancer: A prospective real-world TOG study.

INTRODUCTION: In this study, the toxicities and management of palbociclib and ribociclib in older patients (≥65 years) with metastatic breast cancer patients were investigated. MATERIALS AND METHODS: Among older patients receiving palbociclib and ribociclib, Geriatric 8 (G8) and Groningen Frailty Index were used to evaluate frailty status. Dose modifications, drug withdrawal and other serious adverse events (SAEs) were recorded and analyzed according to baseline patient characteristics. RESULTS: A total of 160 patients from 28 centers in Turkey were included (palbociclib = 76, ribociclib = 84). Forty-three patients were ≥ 75 years of age. The most common cause of first dose modification was neutropenia for both drugs (97% palbociclib, 69% ribociclib). Liver function tests elevation (10%) and renal function impairment (6%) were also causes for ribociclib dose modification. Drug withdrawal rate was 3.9% for palbociclib and 6% for ribociclib. SAEs were seen in 11.8% of those taking palbociclib and 15.5% of those on riboclib. An ECOG performance status of ≥2 and being older than 75 years were associated with dose reductions. Severe neutropenia was more common in patients with non-bone-only metastatic disease, those receiving treatment third-line therapy or higher, coexistance of non-neutropenic hematological side effects (for ribociclib). Neutropenia was less common among patients with obesity. DISCUSSION: Our results show that it can be reasonable to start palbociclib and ribociclib at reduced dose in patients aged ≥75 years and/or with an ECOG performance status ≥2.

Is the Prognostic Nutritional Index a Prognostic Marker for the Survival of Patients with Lymph-Node Positive Stage II-III Gastric Cancer Who Receive Adjuvant Chemotherapy?

PURPOSE: The prognostic nutritional index (PNI), like other systemic inflammatory markers, has been shown to be a prognostic factor in various cancer patients. In this study, we aimed to show whether PNI calculated before adjuvant chemotherapy is a prognostic factor for overall survival (OS) and disease-free survival (DFS) in patients with lymph node-positive stage II-III gastric cancer. METHODS: The PNI was calculated using the albumin and lymphocyte count. The PNI cut-off value was found to be 39.5. They were divided into two groups as being ≤ 39.5 (PNI low group) and > 39.5 (PNI high group). RESULTS: Our study included 168 patients with lymph node-positive stage II-III gastric cancer who received adjuvant chemotherapy. Of the patients, 116 (69.0%) were 65 years or younger, and 52 (31.0%) were over 65 years old. Of the patients, 117 (69.6%) were pT3, 51 (30.4%) were pT4. Seventy-three (43.4%) patients had pN1-2 disease and 95 (56.6%) patients had pN3 disease. The number of stage II patients was 73 (43.5%) and the number of stage III patients was 95 (56.5%). There were 73 patients with PNI ≤ 39.5 and 95 patients with PNI > 39.5. The mOS of the patients with low PNI group was 39.5 months, while the OS of the patients with high PNI group was 96.8 months (p = 0.002). In the group of patients with PNI low group, mDFS 24.4 months was significantly higher than those with PNI high group was 50.7 months (p = 0.021). The PNI score was statistically significant in univariate and multivariate analyzes for both DFS and OS. CONCLUSION: PNI can be used as an independent prognostic factor for both OS and DFS in patients lymph node-positive, stage II-III gastric cancer who will receive adjuvant chemotherapy.

Low-dose (7.5 mg/kg) bevacizumab may be a viable option in recurrent ovarian cancer: A retrospective study.

Objective: Bevacizumab (BEV) is a humanized monoclonal antibody of vascular endothelial growth factor receptors and, as a result of clinical trials, was approved for the treatment of recurrent ovarian cancer (ROC). The aim of this study was to assess the clinical utility of BEV in patients with ROC in real-world practice beyond clinical trials. Materials and Methods: In this single-center retrospective cohort study, we evaluated the medical data of all patients with ROC who were treated with BEV between October 2013 and March 2020. Results: A total of 76 females were evaluated. Forty-nine (64.5%) patients were platinum sensitive and 27 (35.5%) patients were platinum resistant. BEV was used in combination with chemotherapy agents in all patients, and the most preferred combinations were gemcitabine/carboplatin (GC) (78.9%) and carboplatin/paclitaxel (14.5%). In all patients, the BEV dose was 7.5 mg/kg every 3 weeks. The median progression-free survival (PFS) was 11.1 months (95% confidence interval [CI]: 9.6-12.6), and the median overall survival (OS) was 22.3 months (95% CI: 17.5-27.2). In multivariate analysis, serous histological type (P = 0.01), maintenance BEV administration (P = 0.001), and combination of GC-BEV (P < 0.001) were associated with better PFS, while serous histological type (P = 0.016) and good performance status (P = 0.006) were associated with prolonged OS. Conclusions: Low-dose (7.5 mg/kg) BEV was found to be effective in the second-line treatment of patients with ROC in our real-life study. In addition, the combination of BEV with GC was shown to be a viable option, especially in the treatment selection of platinum-resistant patients.

Sunitinib-induced small bowel wall edema as a prognostic marker in metastatic renal cell carcinoma.

Aim: The aim of this study was to evaluate the presence of small bowel wall edema (SBWE) on computed tomography (CT) images in patients with metastatic renal cell carcinoma (mRCC) treated with sunitinib and to investigate the relationship between the presence of SBWE and survival. Materials and Methods: We retrospectively evaluated the presence of SBWE on CT images of 27 mRCC patients who received at least one cycle of sunitinib. Then, we analyzed the relationship between the presence of SBWE and progression-free survival (PFS) and overall survival (OS). RESULTS: All 27 patients had SBWE on at least one CT scan. The median value of SBWE thickness was 2.5 mm. SBWE thickness was ≤2.5 mm in 13 patients (group A) and >2.5 mm in 14 patients (group B). The median OS was significantly higher in group B (55 vs. 18 months, respectively, P = 0.02). Although it was not statistically significant (13 vs. 8 months, respectively, P = 0.69), the median PFS was longer in group B than in group A. CONCLUSIONS: This study showed that sunitinib treatment caused SBWE in all patients with mRCC who received the drug. Also, this study demonstrated an association between higher SBWE thickness and better survival outcomes.

Prognostic biomarkers in metastatic colorectal cancer: delta prognostic nutritional index, delta neutrophil to lymphocyte ratio, and delta platelet to lymphocyte ratio.

BACKGROUND: The aim of this study is to determine the prognostic value of the prognostic nutritional index (PNI), the neutrophil to lymphocyte ratio (NLR), and the platelet to lymphocyte ratio (PLR) and their dynamic changes on survival outcomes in metastatic colorectal cancers (mCRC). METHODS: The data of 199 patients with mCRC were retrospectively analyzed. To evaluate the temporal relation between the PNI, NLR, and PLR values and survival, pre-chemotherapy PNI, NLR, and PLR levels were assessed from peripheral blood cell counts on admission; post-chemotherapy PNI, NLR, and PLR levels were assessed with follow-up blood cell counts within two weeks after chemotherapy; and the difference between pre-chemotherapy PNI, NLR, and PLR levels and post-chemotherapy PNI, NLR, and PLR levels was evaluated as delta PNI, delta NLR, and delta PLR. RESULTS: The median PNI, PLR, and NLR were 39.01, 150.2 and 2.53 before chemotherapy and 38.2, 146.6, and 3.31 after chemotherapy, respectively. The median OS was 23.7 months (95%CI:17.8-29.7) and 28.9 months (95%CI:24.8-33.08) for pre-chemotherapy PNI level < 39.01 vs. PNI level ≥ 39.01, respectively(p = 0.035) The positive delta PNI was significantly higher for OS than the negative delta PNI(p < 0.009). Delta PLR and delta NLR were not significant for OS and PFS(p > 0.05 for all). CONCLUSIONS: The results of this study clearly show that the negative delta PNI to be an independent predictor of poor OS and poor PFS in patients with colon cancer who received first line treatment. In addition, delta NLR and delta PLR were shown not to predict survival outcomes.

The effect of concomitant proton pump inhibitor use on survival outcomes of Nivolumab-treated renal cell carcinoma patients: a multicenter study.

AIM: We aimed to evaluate the effect of concomitant proton pump inhibitors (PPI) use with nivolumab on survival outcomes in metastatic renal cell carcinoma (mRCC) in second-line setting. METHODS: The study was designed as a multicenter and retrospective involving patients with metastatic renal cell carcinoma receiving second-line nivolumab therapy. One hundred and nine patients with mRCC were divided into two groups based on whether they use PPI concomitantly with nivolumab: concomitant PPI users and non-users. Overall survival (OS) and progression-free survival (PFS) were compared between the groups with and without concurrent PPIs. RESULTS: Of 109 patients in our study, 59 were not using PPI concomitantly with nivolumab and 50 were using PPI concomitantly. The median PFS was 6.37 (5.2-7.5) months in the concomitant PPI group and 9.7 (4.5-15) months in the non-users (p = 0.03). The median OS was 14.6 (7.1-22.1) months in patients on PPI concurrently with nivolumab and 29.9 (17.1-42.7) months in the non-users (p = 0.01). Accordingly, PPI use for PFS (Non-use vs. Use = HR: 0.44, 95%Cl 0.28-0.96, p = 0.014) and PPI use for OS (Non-use vs. Use = HR: 0.68, 95%Cl 0.22-0.88, p = 0.01) were found to be as independent risk factors. CONCLUSIONS: Concomitant use of PPIs is associated with worse survival outcomes in patients with mRCC treated with nivolumab. Clinicians should carefully consider the concomitant use of PPIs in such patients.

The Effect of RAS/BRAF Mutation Status on Prognosis and Relapse Pattern in Early Stage Colon Cancers.

PURPOSE: It is known that the RAS and BRAF mutations are predictive for targeted therapies in treating metastatic colon cancer and negatively affect the prognosis of the disease. However, there are limited studies in early-stage colon cancer about the relationship of this mutational condition with the prognosis and relapse pattern of the disease. In this study, we evaluated the effects of mutational status on the clinical pattern of recurrence and survival in early-stage colon cancer in addition to classical risk factors. METHODS: Patients with early-stage colon cancer at the first time of diagnosis and developing recurrence or metastasis on following up were included in this study. Patients were divided into two groups according to the at the time of relapse RAS/BRAF mutation status: mutant or non-mutant/wild types. Then, mutation analysis was performed again from the early-stage tissue of the patients if available. The relationship between early-stage mutation status and progression-free survival (PFS), overall survival (OS), and relapse pattern was analyzed. RESULTS: The number of patients with mutant and non-mutations in the early stage was 39 and 40, respectively. Mutant and non-mutant patients with stage 3 disease were similar (69% and 70%, respectively). OS (47.27 months vs. 67.53 months; p = 0.02) and PFS (25.12 vs. 38.13 months; p = 0.049) were statistically significantly lower in mutant patients, respectively. Most patients had distant metastases on both sides at recurrence (61.5% vs. 62.5%, respectively). There was no significant difference between mutant and non-mutant patients regarding distant metastasis and local recurrence rates (p = 0.657). A discordance of 11.4% between early-stage and late-stage tissue mutation status. CONCLUSION: The presence of mutation in early-stage colon cancer is associated with shorter OS and PFS. The mutational status did not have a significant effect on the recurrence pattern. Because of the discordance of early-stage and late-stage mutational status, it is recommended to perform mutation analysis from tissue at relapse.

Does red blood cell distribution width predict prognosis in metastatic renal cell carcinoma patients using first-line vascular endothelial growth factor receptor tyrosine kinase inhibitor therapy?

Aim: It is red cell distribution width (RDW) that has been reported to show an inflammatory response which has been studied recently. The aim of this study is to investigate whether the pre-treatment RDW in patients using first-line vascular endothelial growth factor tyrosine kinase inhibitor (VEGFR TKI) with the diagnosis of metastatic renal cell carcinoma (mRCC) predicts treatment response and is a prognostic factor or not. Methods: About 92 patients diagnosed with mRCC who were being treated with sunitinib or pazopanib in the first line between January 2015 and June 2021 were included in the study. The patients were divided into 2 groups, as being ≤15.3 and >15.3, according to the RDW cut-off value calculated by ROC analysis. Results: The mOS of patients with a RDW of ≤15.3% was 45.0 (30.0-59.9) months, and of 21.3 (10.4-32.2) in those with a RDW of >15.3%. This difference was statistically significant (p < 0.001). In the group of patients with a RDW of ≤15.3, median progression free survival (mPFS) (38.04 [16.3-59.7] months) was found to be significantly higher than those with a RDW of >15.3 (17.1 [11.8-22.5] months) (p = 0.04). In multivariate analysis, RDW level (≤15.3, >15.3), was determined to be prognostic markers (p = 0.022). Conclusion: In mRCC patients, the RDW value measured before first-line VEGFR TKI therapy is an independent prognostic marker.

Ribociclib-induced hepatotoxicity.

INTRODUCTION: Cyclin-dependent kinase (CDK) 4/6 inhibitors have shown a different adverse effect. In this case, persistent grade 3 hepatoxicity was observed after ribociclib. Therefore, ribociclib therapy was stopped, and then palbociclib was introduced. Transaminase levels returned to normal by switching to palbociclib therapy. CASE REPORT: 71-year-old postmenopausal female patient with luminal subtypes of metastatic breast cancer treated with ribociclib. MANAGEMENT & OUTCOME: Grade 3 hepatotoxicity secondary to ribociclib developed. She was successfully treated with palbociclib 125 mg. DISCUSSION: In our case, palbociclib was started with a full dose, to increase treatment success. Starting with a 125 mg dose was not cause any toxicity. Nevertheless, laboratory follow-up is required in terms of neutropenia and increased transaminases.

The prognostic role of HIF-1α and NF-κB expression in RAS wild-type metastatic colorectal cancer: A Turkish Oncology Group (TOG) study.

BACKGROUND: Not all RAS wild-type metastatic colorectal cancer (mCRC) patients experience the same benefit from anti-epidermal growth factor receptor (EGFR) treatments. Studies have shown that nuclear factor-κB (NF-κB), hypoxia-inducible factor-1α (HIF-1α), interleukin 8 (IL-8) and transforming growth factor ß (TGF-ß) may be therapeutic targets for mCRC. The aim of this study was to clarify the prognostic value of NF-κB, HIF-1α, IL-8, and TGF-ß expression in patients with left-sided mCRC receiving EGFR inhibitors. METHODS: Patients with RAS wild-type, left-sided mCRC treated with anti-EGFR on the first line between September 2013 and April 2022 were included. Immunohistochemical staining for NF-κB, HIF-1α, IL-8 and TGF-ß was performed from tumor tissues of 88 patients. Patients were divided into NF-κB, HIF-1α, IL-8 and TGF-ß expression positive and negative group, moreover, expression positive group were also divided into two group as expression intensity low and high group. The median follow-up was 25.2 months. RESULTS: Median progression-free survival (PFS) was 8.1 (6-10.2) months in the cetuximab group, 11.3 (8.5-14) months in the panitumumab group (p = 0.09). Median overall survival (OS) was 23.9 (4.3-43.4) months in the cetuximab group, 26.9 (15.9-31.9) months in the panitumumab group (p = 0.8). Cytoplasmic NF-κB expression was present in all patients. The mOS was 19.8 (11-28.6) months in NF-κB expression intensity low group and 36.5 (20.1-52.8) months in high group (p = 0.03). The mOS of the HIF-1α expression negative group was significantly longer compared with expression positive group (p = 0.014). There was no significant difference in IL-8 and TGF-ß expression status on mOS and mPFS (for all, p > 0.05). Positive expression of HIF-1α was poor prognostic for mOS in the univariate analysis (HR:2.7, 95% CI 1.18-6.52, p = 0.02) and in multivariate analysis (HR 3.69, 95% CI 1.41-9.6, p = 0.008). High cytoplasmic expression intensity of NF-κB was found to have a good prognostic value for mOS (HR 0.47, 95% CI 0.26-0.85, p = 0.01). CONCLUSION: High cytoplasmic expression intensity of NF-κB and negative expression of HIF-1α could be a good prognostic marker for mOS in RAS wild-type left-sided mCRC.

Could the concomitant use of beta blockers with bevacizumab improve survival in metastatic colon cancer?

AIM: Drug-drug interactions are sometimes neglected in oncology practice. Due to drug pharmacokinetic and pharmacodynamic interactions, clinically increased or decreased drug effects and increased or decreased adverse effects may occur. Considering that the concomitant use of these two drugs that affect vascular endothelial growth factor receptor (VEGFR) may cause pharmacological potentiation or additive interaction, we aimed to evaluate the survival outcomes of concomitant use of bevacizumab and beta blockers in patients with metastatic colorectal cancer (mCRC). METHODS: In total, 181 patients with mCRC administered with bevacizumab plus cytotoxic chemotherapy regimen in a first-line setting were divided into two groups: concomitant beta-blocker user and nonuser. RESULTS: The median overall survival (mOS) was 35.9 (95% CI: 27.9-43.9) months in the beta-blocker-using group and 29.6 (95% CI: 27.9-43.9) months in the beta-blocker-non-using group (p = 0.054). The median progression-free survival (mPFS) was 16.1 (95% CI: 12.4-19.9) months in the beta-blocker-using group and 12.8 (95% CI: 10.6-15.0) months in the beta-blocker-non-using group (p = 0.006). The multivariate analysis revealed that beta-blocker use was an independent predictor of mPFS (HR: 0.66, 95% CI: 0.46-0.93, p = 0.018) and mOS (HR: 0.57, 95% CI: 0.36-0.91, p = 0.02). CONCLUSION: This study demonstrated that concomitant usage of beta blockers improved both survival outcomes, irrespective of the kind of beta blocker.

The effect of concomitant use of proton pump inhibitors with CDK 4/6 inhibitors on survival in metastatic breast cancer.

AIM: To evaluate the difference of progression free survival between the patients using concomitant proton pump inhibitors and non-users in the patients using CDK 4/6 inhibitors with HR + and HER2 negative mBC. METHODS: We included 86 patients with HR + and HER 2 negative mBC treated with CDK 4/6 inhibitors in this study. Patients were divided into two categories according to their status of PPI use. The primary end points was progression free survival (PFS). We compared PPI users and non-users. RESULTS: Forty-five (52.3%) patients used a PPI concomitantly with a CDK 4/6 inhibitor, and 41 (47.7%) did not. The median duration of follow-up was 10.68 (1.94-27.56) months. Of the patients, 50 (58.1%) palbociclib and 36 (41.9%) received ribociclib. The median progression free survival (mPFS) was 10.9 months (95% CI: 7.5-14.27) in the group with concomitant PPI use with a CDK 4/6 inhibitor, whereas the median progression free survival could not be reached in the group without concomitant PPI use (p = 0.04). In addition, concomitant PPI use with palbociclib was associated with a shorter PFS; there was no significant difference between the concomitant PPI users and non-users in terms of PFS in the patients using ribociclib. CONCLUSION: Palbociclib and ribociclib are weak base drugs so their bioavailability is pH-dependent. PPIs can affect their solubility and their concentration in the plasma. Therefore, we must avoid concomitant use of PPIs and CDK 4/6 inhibitors. If we need to use concomitant PPI and CDK 4/6 inhibitors, we should prefer ribociclib than palbociclib.