Worse Relapse-free Survival In Patients Research Articles

The association of body composition and outcomes following autologous hematopoietic stem cell transplantation in patients with non-Hodgkin lymphoma.

Recently there has been a growing interest in evaluating body composition as a marker for prognosis in cancer patients. The association of body composition parameters and outcomes has not been deeply investigated in patients with autologous hematopoietic stem cell transplantation (HSCT) recipients with non-Hodgkin lymphoma (NHL). We conducted a retrospective cohort study of 264 NHL patients who received autologous HSCT. PreHSCT abdominal CT scans at the levels of L3 were assessed for body composition measures. We evaluated sarcopenia, myosteatosis, high visceral adipose tissue (VAT) and high visceral adipose tissue density (VATD). Using multivariable Cox proportional regression, we analyzed the association of clinical and transplant-related characteristics with overall survival (OS), relapse-free survival (RFS), and non-relapse mortality (NRM). In a multivariate regression model, patients with higher VATD had worse OS (HR 1.78; 95% confidence intervals CI 1.08-2.95, p = 0.02) and worse NRM (HR 2.31 95% CI 1.08-4.95, p = 0.02) than with lower VATD. Patients with lower levels of VAT also had worse RFS (HR 1.49 95% CI 1.03-2.15, p = 0.03). Sarcopenia and myosteatosis were not associated with outcomes. High pre-transplant VATD was associated with lower OS and higher NRM, and low pre-transplant VAT was associated with worse RFS in patients with NHL undergoing autologous HSCT.

Beta-Blocker Use Is Associated With Worse Relapse-Free Survival in Patients With Head and Neck Cancer.

Although beta-blockers (BBs) have been hypothesized to exert a beneficial effect on cancer survival through inhibition of beta-adrenergic signaling pathways, clinical data on this issue have been inconsistent. We investigated the impact of BBs on survival outcomes and efficacy of immunotherapy in patients with head and neck squamous cell carcinoma (HNSCC), non-small-cell lung cancer (NSCLC), melanoma, or squamous cell carcinoma of the skin (skin SCC), independent of comorbidity status or cancer treatment regimen. Patients (N = 4,192) younger than 65 years with HNSCC, NSCLC, melanoma, or skin SCC treated at MD Anderson Cancer Center from 2010 to 2021 were included. Overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS) were calculated. Kaplan-Meier and multivariate analyses adjusting for age, sex, TNM staging, comorbidities, and treatment modalities were performed to assess the effect of BBs on survival outcomes. In patients with HNSCC (n = 682), BB use was associated with worse OS and DFS (OS: adjusted hazard ratio [aHR], 1.67; 95% CI, 1.06 to 2.62; P = .027; DFS: aHR, 1.67; 95% CI, 1.06 to 2.63; P = .027), with DSS trending to significance (DSS: aHR, 1.52; 95% CI, 0.96 to 2.41; P = .072). Negative effects of BBs were not observed in the patients with NSCLC (n = 2,037), melanoma (n = 1,331), or skin SCC (n = 123). Furthermore, decreased response to cancer treatment was observed in patients with HNSCC with BB use (aHR, 2.47; 95% CI, 1.14 to 5.38; P = .022). The effect of BBs on cancer survival outcomes is heterogeneous and varies according to cancer type and immunotherapy status. In this study, BB intake was associated with worse DSS and DFS in patients with head and neck cancer not treated with immunotherapy, but not in patients with NSCLC or skin cancer.

The impact of mesorectal fat area on recurrence following total mesorectal excision for lower rectal cancer.

The mesorectal fat area (MFA) at the tip of the ischial spines on magnetic resonance imaging has been used to characterize mesorectal morphology. Recent studies reported that a larger MFA correlated with difficulties in rectal cancer surgery. However, the relationship between MFA and rectal cancer prognosis remains unclear. This study evaluated the impact of MFA on recurrence following robotic total mesorectal excision (TME) for rectal cancer. Patients who underwent robotic TME for lower rectal cancer from December 2011 to December 2016 were enrolled. Cox regression analysis was performed to determine variables associated with relapse-free survival (RFS). Patients were divided into groups based on MFA, and RFS was compared. Of 230 patients, 173 (75.3%) were male. The median age was 63years, and median MFA was 19.7 cm2. In multivariate analysis, smaller MFA (hazard ratio [HR], 0.93; 95% confidence interval [CI], 0.88-0.97; p < 0.01), p/yp stage II (HR, 3.81; 95% CI, 1.40-10.35; p < 0.01), and p/yp stage III (HR, 5.35; 95% CI, 1.88-15.27; p < 0.01) were independently associated with worse RFS. Sex, body mass index, and visceral fat area were not correlated with RFS. In the median follow-up period of 60.8months, patients with MFA < 19.7 cm2 had a significantly lower 5-year RFS rate (72.7%) than those with MFA ≥ 19.7 cm2 (85.0%). Smaller MFA was associated with worse RFS in patients undergoing robotic TME for lower rectal cancer. MFA is considered to be a prognostic factor in rectal cancer.

Effect of Germline MEFV Polymorphisms on the Prognosis of Japanese Children with Cancer: A Regional Analysis

Introduction: MEFV is the gene responsible for familial Mediterranean fever. It encodes pyrin, which controls inflammation. Besides, previous studies have reported that some germline MEFV variants were associated with tumour susceptibility. Materials and Methods: The loci of 12 germline MEFV variants were genotyped in 153 Japanese children with cancer, and the frequencies of these variants among the patient groups were compared with those in the general Japanese population. Additionally, the relationship between these variants and clinical data, including relapse and death, was investigated. Results: Minor allele frequencies did not differ between patients and the general population, or between sex, age at diagnosis, and diagnosis among patients. P369S/R408Q associated with significantly lower relapse-free survival in all patient analyses and in patients with solid tumours. Additionally, although the results were not significant, E148Q/L110P was likely to associate with worse relapse-free survival in patients with solid tumours. Discussion/Conclusion: Despite several limitations, this study provided the novel insight that the germline MEFV variants are associated with the clinical outcome of paediatric cancer.

Clinical Significance of the Expression of Co-Stimulatory Molecule B7-H3 in Papillary Thyroid Carcinoma.

Background: B7-H3, also known as CD276, an important immune checkpoint member of the B7-CD28 family, is confirmed as a promising target after PD-L1 in clinical trials. Although the overexpression of B7-H3 has been associated with invasive metastatic potential and poor prognosis in multiple types of cancer, nothing is known regarding the expression profiles of B7-H3 in papillary thyroid carcinoma (PTC). In this study, we carried out a large-scale analysis of B7-H3 expression in PTC patients and evaluated the potential clinical significance of B7-H3. Methods: In total, data from 1,210 samples, including 867 cases from TCGA and four GEO datasets, were collected for B7-H3–related transcriptome analyses, and 343 postoperative, whole-tumor sections were collected from patients with PTC at our institute for B7-H3–specific immunohistochemistry (IHC) staining. The statistical analysis was primarily accomplished using the R project for statistical computing. Results: B7-H3 positivity was found in 84.8% of PTC patients (291/343), and the mRNA and protein expression levels of B7-H3 in PTC were markedly higher than those of para-tumor tissues (p < 0.001), demonstrating that B7-H3 can serve as a potential diagnostic biomarker for PTC. The significant upregulation of B7-H3 in PTC is caused by distinct patterns of CNVs and CpG DNA methylation. Functional enrichment analysis confirmed that high B7-H3 expression was significantly associated with specific immune features and angiogenesis. High B7-H3 protein expression was associated with tumor size (p = 0.022), extrathyroidal extension (ETE) (p = 0.003), and lymph node metastasis (LNM) (p < 0.001). More importantly, multivariate analysis confirmed that B7-H3 was an independent predictor of relapse-free survival (RFS) (p < 0.05). In the subgroup analysis, positive B7-H3 staining was associated with worse RFS in patients with primary tumor size ≥2 cm (p < 0.05), age ≥55 years (p < 0.05), LNM (p = 0.07), multifocality (p < 0.05), and ETE (p < 0.05). In addition, Circos plots indicated that B7-H3 was significantly associated with other immune checkpoints in the B7-CD28 family. Conclusion: This is the first comprehensive study to elucidate the expression profile of B7-H3 in PTC. Our observations revealed that B7-H3 is a novel independent biomarker for predicting LNM and disease recurrence for PTC patients, and it thus may serve as an indicator that could be used to improve risk-adapted therapeutic strategies and a novel target for immunotherapy strategies for patients who undergo an aggressive disease course.

Prognostic significance of hedgehog signaling network-related gene expression in breast cancer patients.

Breast cancer continues to be a serious public health problem. The role of the hedgehog pathway in normal development of the mammary gland as well as in carcinogenesis and progression of breast cancer is the subject of intense investigation, revealing functional interactions with cell surface heparan sulfate. Nevertheless, its influence on breast cancer prognosis, and its relation to specific sulfation motifs in heparan sulfate have only been poorly studied in large patient cohorts. Using the public database KMplotter that includes gene expression and survival data of 3951 patients, we found that the higher expression of SHH, HHAT, PTCH1, GLI1, GLI2, and GLI3 positively influences breast cancer prognosis. Stratifying patients according to the expression of hormone receptors, histological grade, lymph node metastasis, and systemic therapy, we observed that GLI1, GLI2, and GLI3 expression, as well as co-expression of SHH and ELP1 were associated with worse relapse-free survival in patients with HER2-positive tumors. Moreover, GLI1 expression in progesterone receptor-negative tumors and GLI3 expression in grade 3 tumors correlated with poor prognosis. SHH,in a panel of cell lines representing different breast cancer subtypes, and HHAT, PTCH1, GLI1, GLI2, and GLI3 were mostly expressed in cell lines classified as HER2-positive and basal-like. Expression of SHH, HHAT, GLI2, and GLI3 was differentially affected by overexpression of the heparan sulfate sulfotransferases HS2ST1 and HS3ST2 in vitro. Althoughhigh HS2ST1 expression was associated with poor prognosis in KMplotter analysis, high levels of HS3ST2 were associated with a good prognosis, except for ER-positive breast cancer. We suggest the GLI transcription factors as possible markers for the diagnosis, treatment, and prognosis of breast cancer especially in HER2-positive tumors, but also in progesterone receptor-negative and grade-3 tumors. The pathway interaction and prognostic impact of specific heparan sulfate sulfotransferases provide novel perspectives regarding a therapeutical targeting of the hedgehog pathway in breast cancer.

Abstract 3402: The impact of germline single nucleotide polymorphisms (SNPs) in ERBB-family genes and genes associated with homologous recombination deficiency (HRD) on response to taxotere, platinum and trastuzumab (TCH) based therapy in the treatment of HER2-positive breast cancer patients

Abstract BACKGROUND: We have shown that ERBB (EGFR, ERBB2, ERBB and ERBB4) germline single nucleotide polymorphisms (SNPs) have a negative impact on the outcome of trastuzumab treated HER2-positive breast cancer (BC) patients. Currently TCH (taxotere, platinum and trastuzumab) based therapy is used to treat early stage HER2-positive BC. We investigate the importance of germline SNPs in ERBB genes and those genes involved in homologous recombination deficiency (HRD), on how patients respond to TCH therapy. PATIENTS AND METHODS: ERBB/HRD SNPs were identified in a panel of 32 HER2-positive BC patients by next generation sequencing (NGS). Agena MassArray analysis confirmed the genotype of these SNPs in a further 157 women. Kaplan-Meier estimates and Cox regression analysis identified that both ERBB/HRD SNPs were associated with relapse free survival (RFS) in patients who received a TCH based treatment versus those who received alternate therapies. Protein extracted from formalin fixed paraffin embedded tumours (n=60), was run on an RPPA platform to measure expression and phosphorylation of proteins (69 antibodies). Logistical regression identified protein levels associated with the presence/absence of ERBB/HRD SNPs that were significantly associated with RFS. RESULTS: Ten ERBB/HRD SNPs were profiled in 157 trastuzumab treated HER2-positive BC patients. The minor alleles of the ERBB2 (rs1136201), ERBB3 (rs2229046) and BARD1 (rs2070096) SNPs significantly associated with a worse RFS in patients who received TCH based therapy relative to those who had the reference allele (ERBB2: HR=2.67 (CI=1.05-6.78), p=0.04; ERBB3 rs2229046: HR=4.95 (CI=1.91-12.79), p=9.75x10-4; BARD1: HR=3.27 (CI =1.16-9.17), p=0.02). The impact of ERBB/HRD SNPs on RFS was not observed in patients who did not receive TCH treatment. The minor allele of the RNF8 rs2284922 SNP is associated with a worse RFS (RNF8: HR=12.42 (CI =2.00-77.19), p=6.89x10-3) relative to those who had the reference allele only in patients who did not receive TCH treatment. RPPA analysis identified that patients who received TCH therapy and had the minor allele of the ERBB3 SNPs were significantly associated with the expression of HER2, p27 and MEK1/2 (rs2229046; minor allele associated with low expression of p27 (p=7.22x10-3) and with high expression of HER2 (p=6.53x10-3); rs773123, minor allele associated with low expression of p27 (p=5.38x10-4) and with high expression of MEK1/2 (p=6.24x10-3). CONCLUSIONS: The presence of germline ERBB/HRD SNPs may play an important role in how a patient responds to TCH based therapy, and clinical assessment of these SNPs by targeted genetic screening of patients' blood may allow for stratification of patients prior to treatment. Citation Format: Stephen F. Madden, Sinead Toomey, Simon Furney, Malgorzata Milewska, Joanna Fay, Elaine W. Kay, John Crown, Susan Kennedy, Bryan T. Hennessy, Alex J. Eustace. The impact of germline single nucleotide polymorphisms (SNPs) in ERBB-family genes and genes associated with homologous recombination deficiency (HRD) on response to taxotere, platinum and trastuzumab (TCH) based therapy in the treatment of HER2-positive breast cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3402. doi:10.1158/1538-7445.AM2017-3402

Should MMMT of the endometrium/ovary be treated with anthracycline instead of taxane based chemotherapy?

5563 Background: Carcinosarcomas of endometrial (MMMT-E) and ovarian (MMMT-O) origin are rare biphasic tumors, associated with poor prognosis and thought to be epithelial in origin. In view of this, there has been a shift towards carboplatin and paclitaxel rather than anthracycline based chemotherapy regimens which were used when they were treated as “sarcomas”. The purpose of this large retrospective study is to determine whether this change in chemotherapy is associated with better outcomes. Methods: Firstly, clinicopathological features of patients with all stages of MMMT-E (n=103) and -O (n=17) were compared to patients with adenocarcinoma of the endometrium (n=172) and ovary (n=189) in a case-controlled study. Clinicopathological characteristics, FIGO stage, first-line regimens and patient outcomes were analyzed. Secondly, primary tumor specimens of high grade serous ovarian cancers (HGSOC, n=1290) and MMMT-O (n=450) from an independent cohort were analyzed using immunohistochemistry and next generation sequencing to predict response to chemotherapeutic agents. Results: MMMT have a poor prognosis, however, there was a plateau in survival of MMMT-E after 2.5 years in patients with FIGO stage I/II disease, with no recurrence/cancer deaths observed beyond this. There was a statistically significant worse relapse-free survival in patients with MMMT-E treated with carboplatin and paclitaxel compared to carboplatin and anthracyclines (p=0.0011). In the second independent prospective cohort comparing HGSOC versus MMMT-O, both were driven predominantly by p53 mutations. MMMT-O expressed statistically more commonly PI3KCA and KRAS (p=0.015 and 0.018), respectively. Of particular interest, both HGSOC and MMMT-O showed a higher percentage of probability of responding to a combination of carboplatin/anthracyclins (71.2 vs. 73.9%) than carboplatin/taxanes (58.4 vs 39.4%). Conclusions: Patients with MMMT-E and stage I/II have an excellent prognosis if there is no recurrence by 2.5 years. Platinum/anthracyclines regimens appear to be associated with a better outcome than platinum/taxane in MMMT-E and MMMT-O. This could be tested in an international prospective randomized controlled trial.

Morphine does not facilitate breast cancer progression in two preclinical mouse models for human invasive lobular and HER2⁺ breast cancer.

Morphine and other opioid analgesics are potent pain-relieving agents routinely used for pain management in patients with cancer. However, these drugs have recently been associated with a worse relapse-free survival in patients with surgical cancer, thus suggesting that morphine adversely affects cancer progression and relapse. In this study, we evaluated the impact of morphine on breast cancer progression, metastatic dissemination, and outgrowth of minimal residual disease. Using preclinical mouse models for metastatic invasive lobular and HER2 breast cancer, we show that analgesic doses of morphine do not affect mammary tumor growth, angiogenesis, and the composition of tumor-infiltrating immune cells. Our studies further demonstrate that morphine, administered in the presence or absence of surgery-induced tissue damage, neither facilitates de novo metastatic dissemination nor promotes outgrowth of minimal residual disease after surgery. Together, these findings indicate that opioid analgesics can be used safely for perioperative pain management in patients with cancer and emphasize that current standards of "good clinical practice" should be maintained.