Analysis of mismatch repair (MMR) proteins expression in a series of malignant pleural mesothelioma (MPM) patients.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e20062-e20062
Author(s):  
Susana Cedres ◽  
Santiago Ponce Aix ◽  
Ana Callejo ◽  
Nuria Pardo ◽  
Alejandro Navarro ◽  
...  
Keyword(s):  
Protein Expression ◽  
Survival Data ◽  
Cox Regression ◽  
Asbestos Exposure ◽  
Performance Status ◽  
Predictive Biomarkers ◽  
University Hospital ◽  
Tumor Biomarker ◽  
Neutrophil Lymphocyte Ratio ◽  
Mmr Proteins

e20062 Background: The increasing incidence and poor outcome associated with MPM demand identification of effective treatment options. Promising results have been reported with immunotherapy (IO) in a small proportion of MPM patients (p). MMR deficiency (dMMR) has been well described in several malignancies and was recently approved as a tumor biomarker for IO with anti-PD-1 checkpoint inhibitor. Next generation sequencing (NGS) data demonstrated that 2% of MPM harbor microsatellite instability. The aim of this study is to characterize MMR by immunohistochemistry (IHC) in a series of MPM p. Methods: Tumors of 159 MPM p from Vall d´Hebron University Hospital and October 12th University Hospital diagnosed between 2002 and 2017 were reviewed. Formalin-fixed, paraffin-embedded tissue was stained for MLH1, MSH2, MSH6 and PMS2 and tumors were classified as dMMR when any MMR protein expression was negative and MMR intact when all MMR proteins were positively expressed. Associations between clinical variables and outcome were assessed with Cox regression models and survival data were calculated by the Kaplan-Meier method. Results: P characteristics: median age: 69 years (29-88 years), males: 71%, performance status (PS) 1:69%, asbestos exposure: 52%, stage III at diagnosis: 42%, epithelial subtype: 65%, systemic treatment 81% (57% chemotherapy with cisplatin plus pemetrexed in first line), 50% received second line and 28% third line. MMR protein expression was analyzed in 158 samples with enough tissue and was positive in all of the cases. The median overall survival (mOS) in all population was 15 months (m) (13.5-18.8m). In a multivariate model factors associated to improved mOS were PS 0 vs PS2 (13 v 2 m, HR 12.8, p < 0.01), neutrophil-lymphocyte ratio (NLR) < 5 (18 v 9 m in NLR ≥5,HR 1.5, p < 0.05) and epitheliod vs sarcomatoid histology (18 vs 4 m HR 4.7, p < 0.01). Thirteen p received IO with anti-CTLA4 or anti-PD-1 blockade in clinical trials, 58% had a response or stable disease for more than 6 m, with median progression-free survival (PFS) of 5.7 m (2.1-26.1m). Conclusions: In our series we were unable to identify any MPM patient with dMMR by IHC. Further studies are needed to elucidate novel predictive biomarkers benefit from IO in MPM.

Analysis of chemotherapy efficacy according to histology in malignant pleural mesothelioma (MPM) patients (p).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e20563-e20563
Author(s):  
Susana Cedres Perez ◽  
Juan David Assaf Pastrana ◽  
Patricia Iranzo ◽  
Ana Callejo ◽  
Nuria Pardo ◽  
...  
Keyword(s):  
Prognostic Factor ◽  
Survival Data ◽  
Cox Regression ◽  
Asbestos Exposure ◽  
Performance Status ◽  
University Hospital ◽  
First Line ◽  
Neutrophil Lymphocyte Ratio ◽  
The Impact ◽  
Line Chemotherapy

e20563 Background: MPM is a highly aggressive pleural tumor associated with asbestos exposure and with limited survival despite systemic therapy. Histology is a prognostic factor and recently CheckMate 743 trial demonstrated survival benefit of immunotherapy in first line with some differences in the efficacy of chemotherapy according to histology. However, randomized trials who led to the approval of antifolate in mesothelioma did not include analysis of outcomes by histology. The objective of this study is to characterize the impact of chemotherapy according to histology in p with MPM at our institution. Methods: We review 189 MPM p diagnosed at Vall d´Hebron University Hospital between November 2002 and April 2020. Associations between clinical variables and outcome were assessed with Cox regression models and survival data were calculated by the Kaplan-Meier method. Results: Patient’s characteristics: median age 68 years (y) (45-88 y), males: 70%, performance status (PS)1: 69%, asbestos exposure: 75%, epithelioid subtype: 76%. First line chemotherapy was offered to 85% of p (66% cisplatin-pemetrexed and 27% carboplatin-pemetrexed). Median overall survival (OS) in overall population was 21.3 m (95%CI17.2-24.3). Epithelioid histology, PS 0, neutrophil-lymphocyte ratio <5 and treatment with cisplatin vs carboplatin were associated with significant improvements in OS (p<0.001). When we analyzed the survival of patients who received first line chemotherapy according to histology, we found that patients with epithelioid tumors had better PFS and OS. Median PFS for p with epithelioid tumors treated with chemotherapy in first line was 4.8 m versus 3.6 months non-epithelioid (HR1.5 CI95% 1.1-2.3; p=0.03). OS of epithelioid p treated with first line chemotherapy was 26.7 m versus 15.0 m non-epithelioid patients (HR2.25 CI95% 1.4-3.4; p<0.001). We analyzed if the differences in survival according to histology were due to type of systemic treatment received (Table). Conclusions: In our series, p with non-epithelioid tumors presented worse prognosis. We confirmed histology is a prognostic factor with better OS for p with epithelioid tumors. Moreover, we demonstrated better efficacy of chemotherapy in epithelioid tumors, although histology is not a predictive factor for the platinum agent sensitivity (p of interaction PFS=0.09, p of interaction OS= 0.65).[Table: see text]

scholarly journals A Comprehensive Analysis of Baseline Clinical Characteristics and Biomarkers Associated with Outcome in Advanced Melanoma Patients Treated with Pembrolizumab

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 168
Author(s):  
Gil Awada ◽  
Yanina Jansen ◽  
Julia Katharina Schwarze ◽  
Jens Tijtgat ◽  
Lennert Hellinckx ◽  
...  
Keyword(s):  
Survival Data ◽  
Cox Regression ◽  
Clinical Laboratory ◽  
Performance Status ◽  
Stage Iv ◽  
Absolute Lymphocyte Count ◽  
Comprehensive Analysis ◽  
Advanced Melanoma ◽  
University Hospital ◽  
Cox Regression Analysis

Background: Pembrolizumab improves the survival of patients with advanced melanoma. A comprehensive analysis of baseline variables that predict the benefit of pembrolizumab monotherapy has not been conducted. Methods: Survival data of patients with advanced melanoma who were treated with pembrolizumab in a single university hospital were collected. A multivariate Cox regression analysis was performed to correlate baseline clinical, laboratory, and radiologic characteristics and NanoString IO360 gene expression profiling (GEP) with survival. Results: 183 patients were included (stage IV 85.2%, WHO performance status ≥1 31.1%; pembrolizumab first-line 25.7%), of whom 112 underwent baseline 18F-FDG-PET/CT imaging, 58 had circulating tumor DNA (ctDNA) assessments, and GEP was available in 27 patients. Active brain metastases, a higher number of metastatic sites, lower albumin and absolute lymphocyte count (ALC), higher C-reactive protein (CRP) and neutrophil-to-lymphocyte ratio, higher total metabolic tumor volume (TMTV), and higher ctDNA levels were associated with worse survival. Elevated lactate dehydrogenase (LDH) ≥ 2ULN (upper limit of normal), CRP ≥ 10ULN, or ALC < 750/mm3 delineate a subpopulation where treatment with pembrolizumab is futile. A TMTV ≥ 80 mL encompassed 17/21 patients with LDH ≥ 2ULN, CRP ≥ 10ULN, or ALC < 750/mm3. No significant associations were observed between baseline GEP scores and survival. Conclusion: Multiple baseline variables correlate with survival on pembrolizumab. TMTV is a more comprehensive baseline biomarker than CRP, LDH, or ALC in predicting the futility of pembrolizumab.

Study of genotypic variations and protein expression of the xCT subunit of cystine/glutamate transporter in pancreatic cancer.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 210-210
Author(s):  
T. J. Huang ◽  
D. Li ◽  
Y. Li ◽  
S. P. Kar ◽  
S. Krishnan ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Overall Survival ◽  
Protein Expression ◽  
Cox Regression ◽  
Performance Status ◽  
Glutamate Transporter ◽  
Supporting Evidence ◽  
Cox Regression Analysis ◽  
Risk Of Death ◽  
Increased Risk

210 Background: The plasma membrane xCT cystine-specific subunit of the cystine/glutamate transporter contributes to chemotherapy resistance in pancreatic cancer by regulating intracellular glutathione levels and protecting cancer cells against oxidative stress. We previously noted that the rs7674870 single nucleotide polymorphism (SNP) of xCT correlated with overall survival in pancreatic cancer and may be predictive of platinum resistance. There are no data regarding xCT protein expression in pancreatic cancer or the functional significance of this SNP. Methods: Paraffin-embedded core and surgical biopsy tumor specimens from 49 patients with metastatic pancreatic adenocarcinoma were analyzed by immunohistochemistry (IHC) using an xCT specific antibody (Novus Biologicals). xCT protein IHC expression scores (product of intensity and percentage of staining cells) were analyzed in relation to overall survival and genotype of the patients using the one factor ANOVA test, Kaplan-Meier plot, log-rank test, and Cox regression analysis. Overall survival was measured from the date of diagnosis to the date of death or last follow-up. Results: Positive xCT expression was detected in 38 (78%) of the 49 samples, and 9 (18%) patients had high levels of expression. High xCT expression was associated with lower overall survival as compared with low expression (5.1 months versus 8.8 months; p = 0.119). In a multivariate Cox regression model with adjustment for prognostic parameters of age, sex, performance status and CA19-9 level, high xCT expression was associated with a 2.1-fold increased risk of death (p = 0.096). Performance status also correlated with overall survival (p = 0.027). Preliminary analysis on the genotype-phenotype association (n = 12) indicated that xCT expression was higher with the TT genotype than the TC/CC genotype (p = 0.115), which is consistent with the previous observation that the TT genotype was associated with reduced survival. Conclusions: These data provide supporting evidence for a possible role of cystine/glutamate transporter xCT subunit in pancreatic cancer progression and survival. Further pharmacogenomic and clinicopathologic studies are ongoing. No significant financial relationships to disclose.

Biomarker to cost-effectively harness the technical prowess of palliative radiation: Neutrophil lymphocyte ratio (NLR) and overall survival following palliative radiotherapy in an unselected real-world population of all tumor sites.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 10111-10111
Author(s):  
Santhanam Sundar ◽  
James Price ◽  
Kirsty Clarke ◽  
Thomas Wolfe ◽  
D Thurairasa ◽  
...  
Keyword(s):  
Overall Survival ◽  
Real World ◽  
Cox Regression ◽  
Palliative Radiotherapy ◽  
Standard Of Care ◽  
University Hospital ◽  
World Population ◽  
Single Fraction ◽  
Neutrophil Lymphocyte Ratio ◽  
Lymphocyte Ratio

10111 Background: Single fraction radiotherapy (RT) is standard of care for palliation of pain from bone metastases (ASTRO IJROBP 2011 79:965). But costly, complex, multi-fraction RT is quite often used for palliation of symptoms from various organs. Health care costs are burgeoning (ASCO JCO 2012 30: 1715). Costs can be constrained by judiciously reducing use of unnecessary multi-fraction RT in pts with limited life expectancy. But radiation oncologists’ ability to predict survival is inaccurate. (Chow IJROBP 2005 61:870). Hence we assessed clinical utility of Neutrophil Lymphocyte ratio (NLR) - a routinely available biomarker. Methods: 233 patients (pts) undergoing palliative RT over a 3 month at Nottingham University Hospital. Predominant Tumour SITES: Lung 28% Breast 13% Prostate 13% Colorectal 9% Gastro-Oesophageal 5% Myeloma 5% Bladder 5%. Predominant HISTOLOGY: Adenocarcinoma 61% Squamous Cell 14%. NLR available for 158 pts. Results: A NLR of 4.5 was highly predictive of 90-day mortality & overall survival in an unselected real world population. (Table). No survival benefit seen for multi-fraction RT over single fraction RT across all tumour sites. On survival analysis by Cox regression, increased NLR was significant with a hazard ratio of 2.2 (95% CI 1.3 to 3.7) whereas total radiation dose, use of multiple fractions , age, serum haemoglobin, serum albumin & histology were not significant. Conclusions: In palliative care of advanced cancer, for pts with high NLR (>4.5), Single fraction RT should be the standard of care for palliation of symptoms. [Table: see text]

scholarly journals Evaluation of the prognostic benefit of identifying the probable primary site in cancer of unknown primary

2015 ◽  
Vol 6 (3) ◽  
pp. 22-28
Author(s):  
Joyutpal Das ◽  
Shahid Gilani
Keyword(s):  
Median Survival ◽  
Cox Regression ◽  
Performance Status ◽  
Disease Onset ◽  
Significant Proportion ◽  
Poor Performance ◽  
Primary Site ◽  
University Hospital ◽  
Unknown Primary ◽  
Poor Performance Status

Abstract With the development of site-specific cancer therapy, identifying the primary origin allows the oncologist to personalise therapy for patients with the cancer of unknown primaries (CUPs). At present, immunohistochemistry (IHC) screening is the standard method used to postulate the primary site in CUP. In this retrospective study, we evaluated the prognostic benefit of identifying the primary site in CUP. All 84 patients who presented with suspected CUP to the Royal Stoke University Hospital between 2011 and 2012 were included in our study. Forty-eight percent (40/84) of these patients were unable to undergo necessary investigations to identify primary sites because of poor performance status. IHC screening was able to postulate the primary site in 59% (26/44) of the remaining patients with confirmed CUP. Therefore, the primary site was not identified in a significant proportion of patients with CUP. The median survival of confirmed CUP with probable primary site was 2.0 months (95% confidence interval (CI): 1.2 to 2.9 months), whereas the median survival of confirmed CUP with no probable primary site was 4.1 months (95% CI: 1.5 to 9.7 months). This difference in survival time was statistically significant. In addition, using the Cox regression model, we found that patients with confirmed CUP with primary sites had prognostically unfavourable diseases with a shorter median survival, regardless of the age of disease onset, gender, sites of metastases or number of metastases. One approach to improve the survival would be to start systemic therapy at the earliest possible opportunity rather than waiting for all investigation results, such as IHC.

Exploratory analysis of angiotensin converting enzyme (ACE) and aldosterone (Ald) serum levels as prognostic and predictive biomarkers on the NCIC CTG BR24 trial.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8048-8048 ◽  
Author(s):  
Jair Bar ◽  
Keyue Ding ◽  
Huijun Zhao ◽  
Scott Andrew Laurie ◽  
Lei Han ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Cox Regression ◽  
Performance Status ◽  
Prognostic Significance ◽  
Predictive Biomarkers ◽  
Serum Levels ◽  
Exploratory Analysis ◽  
Categorical Variables ◽  
Test Time ◽  
P Value

8048 Background: Benefit from angiogenesis inhibitors (AI) has been linked to high blood pressure. One of the main determinants of blood pressure is the renin-angiotensin axis. We undertook an exploratory, retrospective analysis of ACE and Ald serum levels on specimens banked during the conduct of the BR24 study. The aim was to evaluate these markers for their prognostic significance and their predictive value regarding Cediranib (Ced) treatment. Methods: The NCIC CTG BR24 study randomized advanced non-small cell lung cancer patients (pts) to carboplatin and paclitaxel (CP) +/- Ced. ACE and Ald serum levels were retrospectively tested on baseline samples using commercial ELISA kits. A graphic method, differentiating treatment effect by the range of marker, was used to determine cutoff points (JCO 2010, 28: 5247). Exploratory analyses were performed to correlate biomarkers levels with pts characteristics and overall survival (OS). Association between categorical variables was assessed by Chi-square test or Fisher’s exact test; time to event correlation with biomarkers was tested using a Cox regression model. Potential confounding factors including medications were integrated into the statistical model. Results: Biomarker data was available in 226 of 296 randomized pts. The tested pts vs. all the randomized pts were more likely to have a lower performance status (PS, p=0.03), a normal LDH (p=0.05) and to be ever-smokers (p=0.015). The determined cutoffs were ACE: 115ng/ml and Ald: 250 pg/ml. High ACE was associated with a better PS (p=0.03). High ACE levels were prognostic for longer OS (adjusted HR 0.52 [95%C.I. 0.29-0.92], p=0.025). High ACE pts had no OS benefit (HR 1.27 [95% C.I. 0.78–2.08], p=0.34), while low ACE predicted OS benefit from the addition of Ced to CP (HR 0.64 [95%CI 0.42-0.97], p=0.03). Interaction p value=0.03; this remained significant after adjustment in multivariate analyses. Ald levels were neither prognostic nor predictive. Conclusions: This exploratory analysis suggests high ACE serum levels maybe prognostic for better OS, while low ACE may predict benefit from Ced when added to CP.

Outcome analyses in patients with metastatic gastroenteropancreatic neuroendocrine tumors receiving peptide receptor radionuclide therapy with 177Lu-DOTATATE – Impact of treatment order and combination on mortality.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 4606-4606
Author(s):  
Alexander Rheinhard Siebenhuener ◽  
Dominique Pretot ◽  
Valerie Treyer
Keyword(s):  
Neuroendocrine Tumors ◽  
Survival Data ◽  
Odds Ratio ◽  
Pancreatic Tumor ◽  
Performance Status ◽  
Blood Parameters ◽  
University Hospital ◽  
Somatostatin Analogue ◽  
Gastroenteropancreatic Neuroendocrine Tumors ◽  
Significant Deterioration

4606 Background: Neuroendocrine tumors of the gastroenteropancreatic tract present heterogeneous with several systemic treatment options in the advanced setting. PRRT with 177Lu-DOTATATE targeting the SSTR-2 receptor of these tumors showed effective responses in the NETTER-1 trial in the short as well as long term follow-up of patients. The aim of our study was to determine the HRQoL and outcome of GEP-NET patients. Methods: 41 GEP-NET patients who received 177Lu-DOTATATE (mean: 3 cycles) between 2012 and 2017 at University Hospital Zurich (USZ) were included in this retrospective analysis. HRQoL parameters (fatigue, insomnia, loss of appetite, abdominal pain, nausea, emesis, diarrhea, weight loss) were assessed before and after treatment. At least 3 weeks after the last PRRT cycle, data on blood parameters, HRQoL, and overall survival data were extracted from patient records. To determine factors influencing the success of PRRT therapy and survival, we recorded pre- and post-PRRT treatments (e.g. selective internal radiation therapy/SIRT, somatostatin analogue therapy/SSA, TKI or chemotherapy) and the time-point of PRRT in the therapeutic sequence was analyzed. Results: Baseline rates of HRQoL and ECOG performance status were assessed (baseline mean: ECOG 0). PRRT was well tolerated, with most patients reporting no significant deterioration in HRQoL after treatment. Blood parameters (hemoglobin, leucocyte and platelet counts, creatinine) and glomerular filtration rate were not significantly affected by PRRT therapy. The number of previous treatments did not influence survival after PRRT; neither did the length of the time period between first diagnosis and PRRT. Patients with a SIRT treatment prior to PRRT had an elevated mortality odds ratio of 4.083. If SIRT was applied to patients with a pancreatic tumor, the mortality odds ratio was 1.33 compared to patients without a pancreatic tumor. Post-PRRT SSA increased the odds for survival, with a mortality odds ratio of 2.33 for patients without SSA after PRRT. Conclusions: Patients with advanced GEP-NETs may benefit from PRRT with 177Lu-DOTATATE, as this treatment appears to be well tolerated and does not significantly impair the HRQoL or symptom load. SIRT before PRRT seems to lower the chances of response and reduces survival instead using this sequence vice versa. This trend was also seen if SSA was not used after PRRT. But these trends have to be proven in prospective trials.

scholarly journals Reoperation for recurrent glioblastomas: What to expect?

2021 ◽  
Vol 12 ◽  
pp. 42
Author(s):  
Iuri Santana Neville ◽  
Alexandra Gomes dos Santos ◽  
Cesar Cimonari Almeida ◽  
Leonardo Bilich Abaurre ◽  
Samia Yasin Wayhs ◽  
...  
Keyword(s):  
Cox Regression ◽  
Karnofsky Performance Status ◽  
Performance Status ◽  
Survival Rates ◽  
Weibull Model ◽  
University Hospital ◽  
Current Standard ◽  
Weibull Regression ◽  
Cox Regression Analysis ◽  
Kaplan Meier

Background: The current standard treatment for glioblastoma (GBM) is maximal safe surgical resection followed by radiation and chemotherapy. Unfortunately, the disease will invariably recur even with the best treatment. Although the literature suggests some advantages in reoperating patients harboring GBM, controversy remains. Here, we asked whether reoperation is an efficacious treatment strategy for GBM, and under which circumstances, it confers a better prognosis. Methods: We retrospectively reviewed 286 consecutive cases of newly diagnosed GBM in a single university hospital from 2008 to 2015. We evaluated clinical and epidemiological parameters possibly influencing overall survival (OS) by multivariate Cox regression analysis. OS was calculated using the Kaplan–Meier method in patients submitted to one or two surgical procedures. Finally, the survival curves were fitted with the Weibull model, and survival rates at 6, 12, and 24 months were estimated. Results: The reoperated group survived significantly longer (n = 63, OS = 20.0 ± 2.3 vs. 11.4 ± 1.0 months, P < 0.0001). Second, the multivariate analysis revealed an association between survival and number of surgeries, initial Karnofsky Performance Status, and age (all P < 0.001). Survival estimates according to the Weibull regression model revealed higher survival probabilities for reoperation compared with one operation at 6 months (83.74 ± 3.42 vs. 63.56 ± 3.59, respectively), 12 months (64.00 ± 4.85 vs. 37.53 ± 3.52), and 24 months (32.53 ± 4.78 vs. 12.02 ± 2.36). Conclusion: Our data support the indication of reoperation for GBM, especially for younger patients with good functional status. Under these circumstances, survival can be doubled at 12 and 24 months.

Relationship between changes in serum androgen level measured by LC-MS/MS and therapeutic effect after enzalutamide treatment.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 88-88
Author(s):  
Yoshiyuki Miyazawa ◽  
Toshiyuki Nakamura ◽  
Yutaka Takezawa ◽  
Nobuaki Shimizu ◽  
Yasushige Matsuo ◽  
...  
Keyword(s):  
Cox Regression ◽  
Performance Status ◽  
Serum Levels ◽  
University Hospital ◽  
Exploratory Research ◽  
Castration Resistant Prostate Cancer ◽  
Ecog Performance Status ◽  
Cox Regression Analysis ◽  
Increase Rate ◽  
Androgen Levels

88 Background: Enzalutamide (ENZ) has proven efficacy against castration-resistant prostate cancer (CRPC) and is widely used in treatment. However, no useful biomarkers have yet been reported to predict the effects of ENZ. We examined the relationship between the efficacy of ENZ and changes in serum androgen levels after ENZ administration. Methods: This exploratory research was based on the data from our prospective clinical trial. Of a total of 104 cases, 67 with confirmed changes in androgen levels after 3 months of ENZ administration, compared to pretreatment levels, were included in this study to identify prognostic factors. Serum androgen levels were measured by liquid chromatography-mass spectrometry (LC-MS/MS). This study was approved by the institutional review board of Gunma University Hospital (No.1177). Results: The study population of 67 patients had a median age of 73 years. The median serum levels of testosterone (T), dihydrotestosterone (DHT), androstenedione (A-dione), and dehydroepiandrosterone sulfate (DHEA-S) before treatment were 56.8 pg/ml, 7.8 pg/ml, 253.5 pg/ml, and 502.2 pg/ml, respectively. The median increase rate(%) of T, DHT, A-dione andDHEA-S after 3 months of ENZ administration were +55.5%, +49.5%, +25.8%, and +24.9%, respectively. T, DHT, and A-dione levels were significantly increased after 3 months (p < 0.05). We performed Cox regression analysis to predict PSA-PFS and OS. Hemoglobin (Hb, ≥ 12.5 g/dl vs. < 12.5 g/dl) and T increase rate ( < 55.5% vs. ≥ 55.5%) were significant predictors of PSA-PFS (p < 0.05). ECOG performance status (0 vs. 1 - 2, respectively) and Hb (≥ 12.5 vs. < 12.5 g/dl, respectively) and T ( < 55.5% vs. ≥55.5%) were significant predictors of OS (p < 0.05). Conclusions: PSA-PFS and OS were significantly poor in the cases in which T increased significantly 3 months after ENZ administration. It was suggested that the change of hormonal environment after ENZ administration may be a prognostic factor.

CCNE1 mRNA and cyclin E1 protein expression as predictive biomarkers for efficacy of palbociclib plus fulvestrant versus capecitabine in the phase III PEARL study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 1014-1014
Author(s):  
Javier Pascual ◽  
Miguel Gil-Gil ◽  
Christoph Zielinski ◽  
Margaret Hills ◽  
Manuel Ruiz-Borrego ◽  
...  
Keyword(s):  
Protein Expression ◽  
Cox Regression ◽  
Statistical Significance ◽  
Predictive Biomarkers ◽  
Phase Iii ◽  
Relative Resistance ◽  
Luminal A ◽  
Luminal B ◽  
Cyclin E1 ◽  
E1 Protein

1014 Background: The randomized PEARL trial found no superiority of palbociclib plus endocrine therapy over capecitabine in patients (pts) with metastatic HR-positive, HER2-negative breast cancer resistant to prior aromatase inhibitors (Martin M, Ann Oncol 2020). Gene expression analysis showed high CCNE1 mRNA ( CCNE1) conferring relative resistance to palbociclib in the PALOMA-3 trial (Turner N, JCO 2019), but further validation is needed. Cyclin E1 protein (cyclin E1) expression in this context has not been studied in randomized trials. We explored CCNE1 and cyclin E1 as predictive biomarkers in tumor samples from the PEARL study. Methods: Formalin-fixed paraffin-embeded tumor samples were retrieved from pts enrolled in PEARL cohort 2 (palbociclib (PAL) + fulvestrant (FUL) vs capecitabine (CAPE)). We measured CCNE1 using the HTG EdgeSeq Oncology Biomarker Panel (HTG Molecular Diagnostics). Cyclin E1 immunohistochemistry (IHC) staining was performed using specific mouse monoclonal antibody HE12 (Abcam) and scored as percentage of invasive nuclei stained (0-100%). CCNE1 and cyclin E1 correlations were explored using Pearson coefficients. Cox regression models were used for progression free-survival (PFS) analyses using expression levels split by median, to define high ( > median values) vs. low expression. Site of disease and prior chemotherapy were used as confounders in multivariate models. Results: Analyses were conducted in 219 pts (47% receiving PAL + FUL and 53% CAPE) with available tumors, with the analysed patients representative of the overall study. Most samples were from the archival primary (72%), obtained > 5 years before this analysisº (74%). CCNE1 and cyclin E1 were only moderately correlated (r = 0.5). Median CCNE1 was higher in metastatic vs primary (7.37 vs 6.94, p < 0.01), and in luminal B and non-luminal subtypes compared to luminal A (p < 0.001). In patients with high CCNE1 expression, median PFS on CAPE was 10.35 and PAL + FUL was 5.68 (HR = 1.63, 95% CI 1.02-2.59, p = 0.042). In patients with low CCNE1 expression, median PFS on CAPE was 9.43 and PAL + FUL was 8.97 (adjusted HR = 0.93, 95% CI 0.59-1.48, p = 0.762, interaction p = 0.072). Median cyclin E1 protein was higher in luminal B and non-luminal subtypes compared to luminal A (p < 0.01). Cyclin E1 protein expression was not predictive of treatment effect (high cyclin E1 expression CAPE vs PAL + FUL HR = 1.17, low cyclin E1 expression CAPE vs PAL + FUL HR = 1.21, interaction p = 0.977). Conclusions: High tumor CCNE1 mRNA expression identified patients with relative resistance to palbociclib plus fulvestrant, validating prior observations although without statistical significance for interaction. Assessment of Cyclin E1 protein expression did not show predictive value. Investigation treatments to enhance CDK4/6 inhibitor efficacy in tumors with high CCNE1 expression is warranted. Clinical trial information: NCT02028507 .

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