Progression-free Survival In Metastatic Patients Research Articles

Automated NLP Extraction of Clinical Rationale for Treatment Discontinuation in Breast Cancer.

Key oncology end points are not routinely encoded into electronic medical records (EMRs). We assessed whether natural language processing (NLP) can abstract treatment discontinuation rationale from unstructured EMR notes to estimate toxicity incidence and progression-free survival (PFS). We constructed a retrospective cohort of 6,115 patients with early-stage and 701 patients with metastatic breast cancer initiating care at Memorial Sloan Kettering Cancer Center from 2008 to 2019. Each cohort was divided into training (70%), validation (15%), and test (15%) subsets. Human abstractors identified the clinical rationale associated with treatment discontinuation events. Concatenated EMR notes were used to train high-dimensional logistic regression and convolutional neural network models. Kaplan-Meier analyses were used to compare toxicity incidence and PFS estimated by our NLP models to estimates generated by manual labeling and time-to-treatment discontinuation (TTD). Our best high-dimensional logistic regression models identified toxicity events in early-stage patients with an area under the curve of the receiver-operator characteristic of 0.857 ± 0.014 (standard deviation) and progression events in metastatic patients with an area under the curve of 0.752 ± 0.027 (standard deviation). NLP-extracted toxicity incidence and PFS curves were not significantly different from manually extracted curves (P = .95 and P = .67, respectively). By contrast, TTD overestimated toxicity in early-stage patients (P < .001) and underestimated PFS in metastatic patients (P < .001). Additionally, we tested an extrapolation approach in which 20% of the metastatic cohort were labeled manually, and NLP algorithms were used to abstract the remaining 80%. This extrapolated outcomes approach resolved PFS differences between receptor subtypes (P < .001 for hormone receptor+/human epidermal growth factor receptor 2- v human epidermal growth factor receptor 2+ v triple-negative) that could not be resolved with TTD. NLP models are capable of abstracting treatment discontinuation rationale with minimal manual labeling.

ER and PI3K Pathway Activity in Primary ER Positive Breast Cancer Is Associated with Progression-Free Survival of Metastatic Patients under First-Line Tamoxifen.

Estrogen receptor positive (ER+) breast cancer patients are eligible for hormonal treatment, but only around half respond. A test with higher specificity for prediction of endocrine therapy response is needed to avoid hormonal overtreatment and to enable selection of alternative treatments. A novel testing method was reported before that enables measurement of functional signal transduction pathway activity in individual cancer tissue samples, using mRNA levels of target genes of the respective pathway-specific transcription factor. Using this method, 130 primary breast cancer samples were analyzed from non-metastatic ER+ patients, treated with surgery without adjuvant hormonal therapy, who subsequently developed metastatic disease that was treated with first-line tamoxifen. Quantitative activity levels were measured of androgen and estrogen receptor (AR and ER), PI3K-FOXO, Hedgehog (HH), NFκB, TGFβ, and Wnt pathways. Based on samples with known pathway activity, thresholds were set to distinguish low from high activity. Subsequently, pathway activity levels were correlated with the tamoxifen treatment response and progression-free survival. High ER pathway activity was measured in 41% of the primary tumors and was associated with longer time to progression (PFS) of metastases during first-line tamoxifen treatment. In contrast, high PI3K, HH, and androgen receptor pathway activity was associated with shorter PFS, and high PI3K and TGFβ pathway activity with worse treatment response. Potential clinical utility of assessment of ER pathway activity lies in predicting response to hormonal therapy, while activity of PI3K, HH, TGFβ, and AR pathways may indicate failure to respond, but also opens new avenues for alternative or complementary targeted treatments.

Correlations between estimating GFR methods and oncological outcomes during cancer chemotherapy

Background: Glomerular filtration rate (GFR) measurements are critical in patients with cancer. A variety of methods are used to calculate the estimated GFR. The aim of this study is to investigate whether there is a correlation between these methods and oncologic outcomes according to the stage and treatment agents. Methods: A total of 153 patients were retrospectively recruited. All GFR measurement methods was determined in all patients, before the first cycle of chemotherapy and before the subsequent administrations. Results: In the study population 40% of whom received platinum-based chemotherapy. In this group, overall survival was statistically significant in patients with a CKD-EPI creatinine value of 65 or greater (p:0.023). When we separated the arms according to the stage, there was no relationship between CKD-EPI Cystatin C and progression-free survival in metastatic patients (p: 0.13). In the non-metastatic group, median DFS was 7 months and OS was 13.9 months in patients with CKD-EPI Cystatine C level above 45 (p:0.005). Conclusions: Both CKD-EPI creatinine and CKD-EPI cystatin C were significantly associated with overall survival and disease-free survival in patients receiving platinum-based chemotherapy. When assessed according to the stage, there was a general survival relationship with CKD-EPI cystatin C in the non-metastatic group and in the other groups there was no significant correlation with the estimated GFR measurements.

Systemic Treatment of Early and Metastatic Breast Cancer

Within the last years significant improvements have been achieved in early and metastatic breast cancer treatment by innovative targeted therapies and new drug combinations. GnRH-analogues have been confirmed as an important part of endocrine treatment in premenopausal patients. Endocrine based strategies including CDK-4/6-Inhibitors substantially improve progression-free survival in metastatic patients. For patients with HER2-positive disease the addition of Pertuzumab to Trastuzumab in combination with chemotherapy has achieved a significant improvement in anti-HER2 therapy in early as well as metastatic breast cancer. For triple-negative disease chemotherapy is still the mainstay of treatment. Immune checkpoint inhibitors represent promising strategies in this cohort, which are currently being evaluated in clinical trials. PARP inhibitors will be available as innovative treatment concept in BRCA1/2 mutation carriers.

A prospective study to assess the clinical utility of serum HER2 extracellular domain in breast cancer with HER2 overexpression.

PurposeWe explored the clinical utility of human epidermal growth factor receptor-2 extracellular domain (HER2/ECD) in patients treated for an invasive breast cancer with HER2 overexpression.MethodsWe prospectively studied HER2/ECD levels in the sera of 334 women included between 2007 and 2014, all treated with trastuzumab. HER2/ECD levels were measured at diagnosis, during treatments, and along the follow-up. We investigated the relationship of HER2/ECD with other clinicopathological parameters at diagnosis, its prognosis value, and its utility during the monitoring of a neoadjuvant treatment and the follow-up.ResultsElevated HER2/ECD at diagnosis correlated positively with parameters associated with tumor aggressiveness. Disease-free survival of non-metastatic patients was significantly shorter in patients with high HER2/ECD at diagnosis (HR = 13.6, 95 % CI 1.6–113.6, P < 0.0001). Progression-free survival of metastatic patients was better for patients with low HER2/ECD (HR = 2.6, 95 % CI 1.2–5.3, P = 0.033). A multivariate analysis revealed that HER2/ECD level at diagnosis was an independent prognosis factor. During neoadjuvant therapy, a significant decrease in HER2/ECD was reported only for the complete histological response group (P = 0.031). During the follow-up, HER2/ECD helped predict relapse, disease progression, and metastases before imaging in 18.6 % cases of the studied cohort.ConclusionsHER2/ECD is a prognosis factor that is valuable in evaluating the neoadjuvant treatment efficiency. HER2/ECD also appears to be a helpful surveillance biomarker for the early diagnosis of relapses and to predict the fate of metastases. This study brings evidences to support the use of HER2/ECD in the management of HER2-positive breast cancer.

Aberrant BLM cytoplasmic expression associates with DNA damage stress and hypersensitivity to DNA-damaging agents in colorectal cancer.

Bloom syndrome is a rare and recessive disorder characterized by loss-of-function mutations of the BLM gene, which encodes a RecQ 3'-5' DNA helicase. Despite its putative tumor suppressor function, the contribution of BLM to human sporadic colorectal cancer (CRC) remains poorly understood. The transcriptional regulation mechanism underlying BLM and related DNA damage response regulation in independent CRC subsets and a panel of derived cell lines was investigated by bioinformatics analysis, the transcriptomic profile, a CpG island promoter methylation assay, Western blot, and an immunolocalization assay. In silico analysis of gene expression data sets revealed that BLM is overexpressed in poorly differentiated CRC and exhibits a close connection with shorter relapse-free survival even after adjustment for prognostic factors and pathways that respond to DNA damage response through ataxia telangiectasia mutated (ATM) signaling. Functional characterization demonstrated that CpG island promoter hypomethylation increases BLM expression and associates with cytoplasmic BLM mislocalization and increased DNA damage response both in clinical CRC samples and in derived cancer cell lines. The DNA-damaging agent S-adenosylmethionine suppresses BLM expression, leading to the inhibition of cell growth following accumulation of DNA damage. In tumor specimens, cytoplasmic accumulation of BLM correlates with DNA damage and γH2AX and phosphorylated ATM foci and predicts long-term progression-free survival in metastatic patients treated with irinotecan. Taken together, the findings of this study provide the first evidence that cancer-linked DNA hypomethylation and cytosolic BLM mislocalization might reflect compromised levels of DNA-repair activity and enhanced hypersensitivity to DNA-damaging agents in CRC patients.

Trastuzumab mediates antibody-dependent cell-mediated cytotoxicity and phagocytosis to the same extent in both adjuvant and metastatic HER2/neu breast cancer patients

BackgroundMonoclonal antibodies (mAb), such as trastuzumab are a valuable addition to breast cancer therapy. Data obtained from neoadjuvant settings revealed that antibody-dependent cell-mediated cytotoxicity (ADCC) is a major mechanism of action for the mAb trastuzumab. Conflicting results still call into question whether disease progression, prolonged treatment or concomitant chemotherapy influences ADCC and related immunological phenomena.MethodsWe analyzed the activity of ADCC and antibody-dependent cell-mediated phagocytosis (ADCP) of peripheral blood mononuclear cells (PBMCs) from human epidermal growth factor receptor 2 (HER2/neu) positive breast cancer patients receiving trastuzumab therapy either in an adjuvant (n = 13) or metastatic (n = 15) setting as well as from trastuzumab treatment-naive (t-naive) HER2/neu negative patients (n = 15). PBMCs from healthy volunteers (n = 24) were used as controls. ADCC and ADCP activity was correlated with the expression of antibody binding Fc-gamma receptor (FcγR)I (CD64), FcγRII (CD32) and FcγRIII (CD16) on CD14+ (monocytes) and CD56+ (NK) cells, as well as the expression of CD107a+ (LAMP-1) on CD56+ cells and the total amount of CD4+CD25+FOXP3+ (Treg) cells. In metastatic patients, markers were correlated with progression-free survival (PFS).ResultsADCC activity was significantly down regulated in metastatic, adjuvant and t-naive patient cohorts as compared to healthy controls. Reduced ADCC activity was inversely correlated with the expression of CD107a on CD56+ cells in adjuvant patients. ADCC and ADCP activity of the patient cohorts were similar, regardless of treatment duration or additional chemotherapy. PFS in metastatic patients inversely correlated with the number of peripheral Treg cells.ConclusionThe reduction of ADCC in patients as compared to healthy controls calls for adjuvant strategies, such as immune-enhancing agents, to improve the activity of trastuzumab. However, efficacy of trastuzumab-specific ADCC and ADCP appears not to be affected by treatment duration, disease progression or concomitant chemotherapy. This finding supports the application of trastuzumab at any stage of the disease.

Colorectal Cancer: Focus on Capecitabine

Capecitabine is an oral pro-drug of 5-fluorouracil (5FU) that has demonstrated an efficacy at least equivalent to standard leucovorin (LV)-modulated 5FU I.V. bolus regimen in the management of metastatic colorectal cancer (MCRC) patients as well as in the adjuvant setting. Despite a mild increase of some side effects, capecitabine is usually better tolerated than 5FU/LV, and could be preferable in the treatment of elderly patients. Moreover, usually the patients compliance with an oral treatment is better than with a regimen requiring the placement of a central venous catheter and infusional devices. The combination of capecitabine with oxaliplatin (XELOX regimen) was shown to be as effective as the combination of 5FU/LV with oxaliplatin (FOLFOX4 regimen) in MCRC. The XELOX regimen represents now a new standard of care for MCRC patients, and it will be probably considered in the next future an “user-friendly” alternative to the FOLFOX4 also in resected patients. The addition of bevacizumab to the XELOX regimen was demonstrated to further prolong the progression-free survival of metastatic patients, and is anticipated to reduce the risk of recurrence in resected colon cancer. Despite a higher acquisition cost than 5FU/LV, capecitabine is also cost-effective, because of the reduced costs for drug administration and management of adverse events.

Cytogenetic Profile Predicts Prognosis of Patients With Clear Cell Renal Cell Carcinoma

The majority of cytogenetic studies in renal cell carcinoma (RCC) have been impaired by small sample size, retrospective character, and lack of a survival end point. We prospectively studied the prognostic impact of cytogenetic abnormalities on a larger cohort of patients having up to 108 months of follow-up. Tumors of 282 patients who underwent nephrectomy for clear cell RCC were cytogenetically analyzed. Results were correlated with pathological factors and disease-specific survival. The most frequently observed cytogenetic abnormalities were loss of 3p (60%), gain of 5q (33%), loss of 14q (28%), trisomy 7 (26%), loss of 8p (20%), loss of 6q (17%), loss of 9p (16%), loss of 4p (13%), and loss of chromosome Y in men (55%). Tumors with loss of 3p presented at lower TNM stages. Loss of 4p, 9p, and 14q were all associated with higher TNM stages, higher grade, and greater tumor size. A deletion of 3p was associated with better prognosis (P = .03), while loss of 4p (P < .001), loss of 9p (P < .01), and loss of 14q (P < .01) were each associated with worse prognosis. Loss of the Y chromosome led to improved progression-free survival in metastatic patients (P = .02). In multivariate analysis, loss of 9p was retained as an independent prognostic factor. This cytogenetic study serves as a proof of principal that genetic information, such as loss of chromosome 9, can be obtained from widely available technology, and can provide additional prognostic information to standard clinicopathologic variables.